[{"date_updated":"2025-09-08T08:15:54Z","title":"Monoallelic de novo AJAP1 loss-of- function variants disrupt trans-synaptic control of neurotransmitter release","abstract":[{"text":"Adherens junction–associated protein 1 (AJAP1) has been implicated in brain diseases; however, a pathogenic mechanism has not been identified. AJAP1 is widely expressed in neurons and binds to γ-aminobutyric acid type B receptors (GBRs), which inhibit neurotransmitter release at most synapses in the brain. Here, we show that AJAP1 is selectively expressed in dendrites and trans-synaptically recruits GBRs to presynaptic sites of neurons expressing AJAP1. We have identified several monoallelic AJAP1 variants in individuals with epilepsy and/or neurodevelopmental disorders. Specifically, we show that the variant p.(W183C) lacks binding to GBRs, resulting in the inability to recruit them. Ultrastructural analysis revealed significantly decreased presynaptic GBR levels in Ajap1−/− and Ajap1W183C/+ mice. Consequently, these mice exhibited reduced GBR-mediated presynaptic inhibition at excitatory and inhibitory synapses, along with impaired synaptic plasticity. Our study reveals that AJAP1 enables the postsynaptic neuron to regulate the level of presynaptic GBR-mediated inhibition, supporting the clinical relevance of loss-of-function AJAP1 variants.","lang":"eng"}],"author":[{"last_name":"Früh","first_name":"Simon","full_name":"Früh, Simon"},{"last_name":"Boudkkazi","first_name":"Sami","full_name":"Boudkkazi, Sami"},{"last_name":"Koppensteiner","id":"3B8B25A8-F248-11E8-B48F-1D18A9856A87","first_name":"Peter","orcid":"0000-0002-3509-1948","full_name":"Koppensteiner, Peter"},{"full_name":"Sereikaite, Vita","last_name":"Sereikaite","first_name":"Vita"},{"full_name":"Chen, Li Yuan","first_name":"Li Yuan","last_name":"Chen"},{"full_name":"Fernandez-Fernandez, Diego","last_name":"Fernandez-Fernandez","first_name":"Diego"},{"first_name":"Pascal D.","last_name":"Rem","full_name":"Rem, Pascal D."},{"full_name":"Ulrich, Daniel","first_name":"Daniel","last_name":"Ulrich"},{"full_name":"Schwenk, Jochen","last_name":"Schwenk","first_name":"Jochen"},{"full_name":"Chen, Ziyang","first_name":"Ziyang","last_name":"Chen"},{"full_name":"Monnier, Elodie Le","last_name":"Monnier","first_name":"Elodie Le"},{"full_name":"Fritzius, Thorsten","first_name":"Thorsten","last_name":"Fritzius"},{"full_name":"Innocenti, Sabrina M.","first_name":"Sabrina M.","last_name":"Innocenti"},{"first_name":"Valérie","last_name":"Besseyrias","full_name":"Besseyrias, Valérie"},{"first_name":"Luca","last_name":"Trovò","full_name":"Trovò, Luca"},{"full_name":"Stawarski, Michal","last_name":"Stawarski","first_name":"Michal"},{"full_name":"Argilli, Emanuela","last_name":"Argilli","first_name":"Emanuela"},{"full_name":"Sherr, Elliott H.","first_name":"Elliott H.","last_name":"Sherr"},{"full_name":"Van Bon, Bregje","last_name":"Van Bon","first_name":"Bregje"},{"full_name":"Kamsteeg, Erik Jan","last_name":"Kamsteeg","first_name":"Erik Jan"},{"full_name":"Iascone, Maria","last_name":"Iascone","first_name":"Maria"},{"first_name":"Alba","last_name":"Pilotta","full_name":"Pilotta, Alba"},{"full_name":"Cutrì, Maria R.","first_name":"Maria R.","last_name":"Cutrì"},{"full_name":"Azamian, Mahshid S.","last_name":"Azamian","first_name":"Mahshid S."},{"full_name":"Hernández-García, Andrés","first_name":"Andrés","last_name":"Hernández-García"},{"last_name":"Lalani","first_name":"Seema R.","full_name":"Lalani, Seema R."},{"first_name":"Jill A.","last_name":"Rosenfeld","full_name":"Rosenfeld, Jill A."},{"full_name":"Zhao, Xiaonan","first_name":"Xiaonan","last_name":"Zhao"},{"last_name":"Vogel","first_name":"Tiphanie P.","full_name":"Vogel, Tiphanie P."},{"full_name":"Ona, Herda","last_name":"Ona","first_name":"Herda"},{"last_name":"Scott","first_name":"Daryl A.","full_name":"Scott, Daryl A."},{"first_name":"Peter","last_name":"Scheiffele","full_name":"Scheiffele, Peter"},{"full_name":"Strømgaard, Kristian","last_name":"Strømgaard","first_name":"Kristian"},{"full_name":"Tafti, Mehdi","last_name":"Tafti","first_name":"Mehdi"},{"first_name":"Martin","last_name":"Gassmann","full_name":"Gassmann, Martin"},{"full_name":"Fakler, Bernd","last_name":"Fakler","first_name":"Bernd"},{"full_name":"Shigemoto, Ryuichi","orcid":"0000-0001-8761-9444","last_name":"Shigemoto","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","first_name":"Ryuichi"},{"full_name":"Bettler, Bernhard","first_name":"Bernhard","last_name":"Bettler"}],"article_number":"adk5462","volume":10,"citation":{"ama":"Früh S, Boudkkazi S, Koppensteiner P, et al. Monoallelic de novo AJAP1 loss-of- function variants disrupt trans-synaptic control of neurotransmitter release. <i>Science Advances</i>. 2024;10(28). doi:<a href=\"https://doi.org/10.1126/sciadv.adk5462\">10.1126/sciadv.adk5462</a>","chicago":"Früh, Simon, Sami Boudkkazi, Peter Koppensteiner, Vita Sereikaite, Li Yuan Chen, Diego Fernandez-Fernandez, Pascal D. Rem, et al. “Monoallelic de Novo AJAP1 Loss-of- Function Variants Disrupt Trans-Synaptic Control of Neurotransmitter Release.” <i>Science Advances</i>. American Association for the Advancement of Science, 2024. <a href=\"https://doi.org/10.1126/sciadv.adk5462\">https://doi.org/10.1126/sciadv.adk5462</a>.","mla":"Früh, Simon, et al. “Monoallelic de Novo AJAP1 Loss-of- Function Variants Disrupt Trans-Synaptic Control of Neurotransmitter Release.” <i>Science Advances</i>, vol. 10, no. 28, adk5462, American Association for the Advancement of Science, 2024, doi:<a href=\"https://doi.org/10.1126/sciadv.adk5462\">10.1126/sciadv.adk5462</a>.","short":"S. Früh, S. Boudkkazi, P. Koppensteiner, V. Sereikaite, L.Y. Chen, D. Fernandez-Fernandez, P.D. Rem, D. Ulrich, J. Schwenk, Z. Chen, E.L. Monnier, T. Fritzius, S.M. Innocenti, V. Besseyrias, L. Trovò, M. Stawarski, E. Argilli, E.H. Sherr, B. Van Bon, E.J. Kamsteeg, M. Iascone, A. Pilotta, M.R. Cutrì, M.S. Azamian, A. Hernández-García, S.R. Lalani, J.A. Rosenfeld, X. Zhao, T.P. Vogel, H. Ona, D.A. Scott, P. Scheiffele, K. Strømgaard, M. Tafti, M. Gassmann, B. Fakler, R. Shigemoto, B. Bettler, Science Advances 10 (2024).","apa":"Früh, S., Boudkkazi, S., Koppensteiner, P., Sereikaite, V., Chen, L. Y., Fernandez-Fernandez, D., … Bettler, B. (2024). Monoallelic de novo AJAP1 loss-of- function variants disrupt trans-synaptic control of neurotransmitter release. <i>Science Advances</i>. American Association for the Advancement of Science. <a href=\"https://doi.org/10.1126/sciadv.adk5462\">https://doi.org/10.1126/sciadv.adk5462</a>","ieee":"S. Früh <i>et al.</i>, “Monoallelic de novo AJAP1 loss-of- function variants disrupt trans-synaptic control of neurotransmitter release,” <i>Science Advances</i>, vol. 10, no. 28. American Association for the Advancement of Science, 2024.","ista":"Früh S, Boudkkazi S, Koppensteiner P, Sereikaite V, Chen LY, Fernandez-Fernandez D, Rem PD, Ulrich D, Schwenk J, Chen Z, Monnier EL, Fritzius T, Innocenti SM, Besseyrias V, Trovò L, Stawarski M, Argilli E, Sherr EH, Van Bon B, Kamsteeg EJ, Iascone M, Pilotta A, Cutrì MR, Azamian MS, Hernández-García A, Lalani SR, Rosenfeld JA, Zhao X, Vogel TP, Ona H, Scott DA, Scheiffele P, Strømgaard K, Tafti M, Gassmann M, Fakler B, Shigemoto R, Bettler B. 2024. Monoallelic de novo AJAP1 loss-of- function variants disrupt trans-synaptic control of neurotransmitter release. Science Advances. 10(28), adk5462."},"intvolume":"        10","day":"12","external_id":{"pmid":["38985877"],"isi":["001280159000022"]},"oa":1,"acknowledgement":"Ajap1HA/HA and Ajap1W183C/+ mice were generated in collaboration with Pawel Pelczar at the center for transgenic models at the University of Basel, Switzerland. We thank the imaging core facility (IMCF, University of Basel) and in particular A. Ferrand for the technical assistance provided on the OMX 3D-SIM microscope.\r\nThis work was supported by a grant from the Swiss National Science Foundation (SNF) to B.B. (31003A-152970, 310030B-201291), an NIH grant to E.A. and E.H.S. (R01NS058721), DFG grants to B.F. (TRR 152 project ID 239283807, FA 332/15-1, 16-1), and grants to P.S. from AIMS-2-TRIALS, which are supported by the Innovative Medicines Initiatives from the European Commission joint undertaking under grant agreement No 777394.","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)"},"article_type":"original","year":"2024","date_created":"2024-07-21T22:01:01Z","article_processing_charge":"Yes","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","publication_status":"published","language":[{"iso":"eng"}],"publication":"Science Advances","type":"journal_article","publisher":"American Association for the Advancement of Science","_id":"17280","oa_version":"Published Version","scopus_import":"1","isi":1,"ddc":["570"],"month":"07","DOAJ_listed":"1","date_published":"2024-07-12T00:00:00Z","has_accepted_license":"1","file_date_updated":"2024-07-22T06:29:27Z","status":"public","issue":"28","pmid":1,"publication_identifier":{"eissn":["2375-2548"]},"file":[{"relation":"main_file","success":1,"content_type":"application/pdf","date_created":"2024-07-22T06:29:27Z","file_id":"17287","access_level":"open_access","date_updated":"2024-07-22T06:29:27Z","creator":"dernst","file_name":"2024_ScienceAdv_Früh.pdf","file_size":7241489,"checksum":"9cbc4501fcd4ba1c0811fd244031422b"}],"doi":"10.1126/sciadv.adk5462","quality_controlled":"1","department":[{"_id":"RySh"},{"_id":"PreCl"}],"OA_place":"publisher","OA_type":"gold","fulldoi":"https://doi.org/10.1126/sciadv.adk5462"},{"article_type":"original","APC_amount":"6248,82 EUR","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)"},"acknowledgement":"We thank Carolina Borges-Merjane, Jing-Jing Chen, Katharina Lichter, and Samuel Young for critically reading the manuscript; the Electron Microscopy Facility of ISTA, in particular Vanessa Zheden, for extensive support, advice, and experimental assistance; the Preclinical Facility of ISTA, in particular Victoria Wimmer and Michael Schunn, for experimental assistance; Florian Marr and Christina Altmutter for technical support; Alois Schlögl for help with analysis; and Eleftheria Kralli-Beller for manuscript editing. We also thank Cordelia Imig for providing Munc13-1cKO-Munc13-2/3(−/−) mutant mice. Part of the work has been published in O.K.’s thesis in partial fulfillment of the requirements for the degree of Doctor of Philosophy.\r\nThis project received funding from the European Research Council and European Union’s Horizon 2020 research and innovation programme (ERC 692692 to P.J.; https://cordis.europa.eu/project/id/692692/de) and from the Fond zur Förderung der Wissenschaftlichen Forschung (Z312-B27 Wittgenstein award to P.J., https://www.fwf.ac.at/en/funding/portfolio/projects/fwf-wittgenstein-award; W1205-B09 and P36232-B to P.J., https://www.fwf.ac.at/en/funding; I6166-B to R.S.; https://www.fwf.ac.at/en/funding). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","external_id":{"pmid":["39556620"],"isi":["001358568700003"]},"oa":1,"article_processing_charge":"Yes","date_created":"2024-12-01T23:01:54Z","year":"2024","author":[{"full_name":"Kim, Olena","orcid":"0000-0003-2344-1039","first_name":"Olena","id":"3F8ABDDA-F248-11E8-B48F-1D18A9856A87","last_name":"Kim"},{"full_name":"Okamoto, Yuji","orcid":"0000-0003-0408-6094","id":"3337E116-F248-11E8-B48F-1D18A9856A87","last_name":"Okamoto","first_name":"Yuji"},{"first_name":"Walter","id":"3F99E422-F248-11E8-B48F-1D18A9856A87","last_name":"Kaufmann","orcid":"0000-0001-9735-5315","full_name":"Kaufmann, Walter"},{"full_name":"Brose, Nils","last_name":"Brose","first_name":"Nils"},{"orcid":"0000-0001-8761-9444","full_name":"Shigemoto, Ryuichi","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","last_name":"Shigemoto","first_name":"Ryuichi"},{"full_name":"Jonas, Peter M","orcid":"0000-0001-5001-4804","first_name":"Peter M","id":"353C1B58-F248-11E8-B48F-1D18A9856A87","last_name":"Jonas"}],"abstract":[{"text":"It is widely believed that information storage in neuronal circuits involves nanoscopic structural changes at synapses, resulting in the formation of synaptic engrams. However, direct evidence for this hypothesis is lacking. To test this conjecture, we combined chemical potentiation, functional analysis by paired pre-postsynaptic recordings, and structural analysis by electron microscopy (EM) and freeze-fracture replica labeling (FRL) at the rodent hippocampal mossy fiber synapse, a key synapse in the trisynaptic circuit of the hippocampus. Biophysical analysis of synaptic transmission revealed that forskolin-induced chemical potentiation increased the readily releasable vesicle pool size and vesicular release probability by 146% and 49%, respectively. Structural analysis of mossy fiber synapses by EM and FRL demonstrated an increase in the number of vesicles close to the plasma membrane and the number of clusters of the priming protein Munc13-1, indicating an increase in the number of both docked and primed vesicles. Furthermore, FRL analysis revealed a significant reduction of the distance between Munc13-1 and CaV2.1 Ca2+ channels, suggesting reconfiguration of the channel-vesicle coupling nanotopography. Our results indicate that presynaptic plasticity is associated with structural reorganization of active zones. We propose that changes in potential nanoscopic organization at synaptic vesicle release sites may be correlates of learning and memory at a plastic central synapse.","lang":"eng"}],"title":"Presynaptic cAMP-PKA-mediated potentiation induces reconfiguration of synaptic vesicle pools and channel-vesicle coupling at hippocampal mossy fiber boutons","date_updated":"2026-04-16T12:20:34Z","day":"18","volume":22,"intvolume":"        22","project":[{"grant_number":"692692","_id":"25B7EB9E-B435-11E9-9278-68D0E5697425","name":"Biophysics and circuit function of a giant cortical glutamatergic synapse","call_identifier":"H2020"},{"grant_number":"Z00312","name":"Synaptic communication in neuronal microcircuits","_id":"25C5A090-B435-11E9-9278-68D0E5697425","call_identifier":"FWF"},{"name":"Mechanisms of GABA release in hippocampal circuits","_id":"bd88be38-d553-11ed-ba76-81d5a70a6ef5","grant_number":"P36232"},{"grant_number":"I06166","_id":"b1b85715-d554-11ed-a5ad-84a07fc9f18e","name":"Structural & functional basis of presynaptic plasticity"},{"call_identifier":"FWF","grant_number":"W01205","_id":"25C3DBB6-B435-11E9-9278-68D0E5697425","name":"Zellkommunikation in Gesundheit und Krankheit"},{"call_identifier":"FWF","name":"FWF Open Access Fund","_id":"3AC91DDA-15DF-11EA-824D-93A3E7B544D1"}],"citation":{"ista":"Kim O, Okamoto Y, Kaufmann W, Brose N, Shigemoto R, Jonas PM. 2024. Presynaptic cAMP-PKA-mediated potentiation induces reconfiguration of synaptic vesicle pools and channel-vesicle coupling at hippocampal mossy fiber boutons. PLoS Biology. 22(11), e3002879.","ieee":"O. Kim, Y. Okamoto, W. Kaufmann, N. Brose, R. Shigemoto, and P. M. Jonas, “Presynaptic cAMP-PKA-mediated potentiation induces reconfiguration of synaptic vesicle pools and channel-vesicle coupling at hippocampal mossy fiber boutons,” <i>PLoS Biology</i>, vol. 22, no. 11. Public Library of Science, 2024.","apa":"Kim, O., Okamoto, Y., Kaufmann, W., Brose, N., Shigemoto, R., &#38; Jonas, P. M. (2024). Presynaptic cAMP-PKA-mediated potentiation induces reconfiguration of synaptic vesicle pools and channel-vesicle coupling at hippocampal mossy fiber boutons. <i>PLoS Biology</i>. Public Library of Science. <a href=\"https://doi.org/10.1371/journal.pbio.3002879\">https://doi.org/10.1371/journal.pbio.3002879</a>","mla":"Kim, Olena, et al. “Presynaptic CAMP-PKA-Mediated Potentiation Induces Reconfiguration of Synaptic Vesicle Pools and Channel-Vesicle Coupling at Hippocampal Mossy Fiber Boutons.” <i>PLoS Biology</i>, vol. 22, no. 11, e3002879, Public Library of Science, 2024, doi:<a href=\"https://doi.org/10.1371/journal.pbio.3002879\">10.1371/journal.pbio.3002879</a>.","short":"O. Kim, Y. Okamoto, W. Kaufmann, N. Brose, R. Shigemoto, P.M. Jonas, PLoS Biology 22 (2024).","chicago":"Kim, Olena, Yuji Okamoto, Walter Kaufmann, Nils Brose, Ryuichi Shigemoto, and Peter M Jonas. “Presynaptic CAMP-PKA-Mediated Potentiation Induces Reconfiguration of Synaptic Vesicle Pools and Channel-Vesicle Coupling at Hippocampal Mossy Fiber Boutons.” <i>PLoS Biology</i>. Public Library of Science, 2024. <a href=\"https://doi.org/10.1371/journal.pbio.3002879\">https://doi.org/10.1371/journal.pbio.3002879</a>.","ama":"Kim O, Okamoto Y, Kaufmann W, Brose N, Shigemoto R, Jonas PM. Presynaptic cAMP-PKA-mediated potentiation induces reconfiguration of synaptic vesicle pools and channel-vesicle coupling at hippocampal mossy fiber boutons. <i>PLoS Biology</i>. 2024;22(11). doi:<a href=\"https://doi.org/10.1371/journal.pbio.3002879\">10.1371/journal.pbio.3002879</a>"},"article_number":"e3002879","pmid":1,"status":"public","file_date_updated":"2024-12-03T08:56:53Z","issue":"11","date_published":"2024-11-18T00:00:00Z","has_accepted_license":"1","fulldoi":"https://doi.org/10.1371/journal.pbio.3002879","OA_type":"gold","department":[{"_id":"PeJo"},{"_id":"EM-Fac"},{"_id":"RySh"}],"OA_place":"publisher","ec_funded":1,"quality_controlled":"1","acknowledged_ssus":[{"_id":"EM-Fac"},{"_id":"PreCl"}],"corr_author":"1","file":[{"date_updated":"2024-12-03T08:56:53Z","creator":"dernst","access_level":"open_access","file_id":"18608","checksum":"7de2dcb50deb65dde05c80082bb85a82","file_size":3057631,"file_name":"2024_PloSBio_Kim.pdf","success":1,"relation":"main_file","date_created":"2024-12-03T08:56:53Z","content_type":"application/pdf"}],"doi":"10.1371/journal.pbio.3002879","publication_identifier":{"issn":["1544-9173"],"eissn":["1545-7885"]},"type":"journal_article","publisher":"Public Library of Science","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","publication_status":"published","language":[{"iso":"eng"}],"publication":"PLoS Biology","related_material":{"record":[{"status":"public","relation":"research_data","id":"18296"}]},"DOAJ_listed":"1","ddc":["570"],"month":"11","scopus_import":"1","_id":"18603","oa_version":"Published Version","isi":1},{"file":[{"file_id":"18297","access_level":"open_access","date_updated":"2024-10-11T10:04:19Z","creator":"okim","file_name":"Kim_et_al_2024_PlosBio_Source_data.zip","checksum":"0a977e7df54c418251b10dfd3f8a015c","file_size":164382,"relation":"main_file","success":1,"content_type":"application/zip","date_created":"2024-10-11T10:04:19Z"},{"content_type":"text/plain","date_created":"2024-10-11T10:04:23Z","relation":"main_file","success":1,"file_name":"info.txt","checksum":"5b9343d6b2035ac3185e390fad4d3830","file_size":654,"file_id":"18298","date_updated":"2024-10-11T10:04:23Z","creator":"okim","access_level":"open_access"}],"doi":"10.15479/AT:ISTA:18296","corr_author":"1","ec_funded":1,"department":[{"_id":"PeJo"},{"_id":"RySh"},{"_id":"EM-Fac"}],"fulldoi":"https://doi.org/10.15479/AT:ISTA:18296","date_published":"2024-10-11T00:00:00Z","has_accepted_license":"1","file_date_updated":"2024-10-11T10:04:23Z","status":"public","keyword":["Hippocampal mossy fiber synapses","short-term potentiation","long-term potentiation","presynaptic plasticity","electron microscopy","freeze-fracture replica labeling","paired recordings","forskolin","cyclic adenosine monophosphate (cAMP)","protein kinase A (PKA)","neuromodulation","synaptic vesicle pools","presynaptic Ca2+ channels","Munc13","docking","priming","active zone"],"_id":"18296","oa_version":"Submitted Version","month":"10","ddc":["570"],"related_material":{"record":[{"status":"public","id":"18603","relation":"used_in_publication"}]},"user_id":"68b8ca59-c5b3-11ee-8790-cd641c68093d","type":"research_data","publisher":"Institute of Science and Technology Austria","date_created":"2024-10-11T10:12:17Z","year":"2024","article_processing_charge":"No","oa":1,"tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)"},"project":[{"call_identifier":"H2020","_id":"25B7EB9E-B435-11E9-9278-68D0E5697425","name":"Biophysics and circuit function of a giant cortical glutamatergic synapse","grant_number":"692692"}],"citation":{"chicago":"Kim, Olena. “Presynaptic CAMP-PKA-Mediated Potentiation Induces Reconfiguration of Synaptic Vesicle Pools and Channel-Vesicle Coupling at Hippocampal Mossy Fiber Boutons.” Institute of Science and Technology Austria, 2024. <a href=\"https://doi.org/10.15479/AT:ISTA:18296\">https://doi.org/10.15479/AT:ISTA:18296</a>.","mla":"Kim, Olena. <i>Presynaptic CAMP-PKA-Mediated Potentiation Induces Reconfiguration of Synaptic Vesicle Pools and Channel-Vesicle Coupling at Hippocampal Mossy Fiber Boutons</i>. Institute of Science and Technology Austria, 2024, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:18296\">10.15479/AT:ISTA:18296</a>.","short":"O. Kim, (2024).","apa":"Kim, O. (2024). Presynaptic cAMP-PKA-mediated potentiation induces reconfiguration of synaptic vesicle pools and channel-vesicle coupling at hippocampal mossy fiber boutons. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:18296\">https://doi.org/10.15479/AT:ISTA:18296</a>","ieee":"O. Kim, “Presynaptic cAMP-PKA-mediated potentiation induces reconfiguration of synaptic vesicle pools and channel-vesicle coupling at hippocampal mossy fiber boutons.” Institute of Science and Technology Austria, 2024.","ista":"Kim O. 2024. Presynaptic cAMP-PKA-mediated potentiation induces reconfiguration of synaptic vesicle pools and channel-vesicle coupling at hippocampal mossy fiber boutons, Institute of Science and Technology Austria, <a href=\"https://doi.org/10.15479/AT:ISTA:18296\">10.15479/AT:ISTA:18296</a>.","ama":"Kim O. Presynaptic cAMP-PKA-mediated potentiation induces reconfiguration of synaptic vesicle pools and channel-vesicle coupling at hippocampal mossy fiber boutons. 2024. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:18296\">10.15479/AT:ISTA:18296</a>"},"day":"11","date_updated":"2026-09-14T08:48:01Z","title":"Presynaptic cAMP-PKA-mediated potentiation induces reconfiguration of synaptic vesicle pools and channel-vesicle coupling at hippocampal mossy fiber boutons","contributor":[{"last_name":"Kim","id":"3F8ABDDA-F248-11E8-B48F-1D18A9856A87","contributor_type":"researcher","first_name":"Olena"},{"orcid":"0000-0003-0408-6094","contributor_type":"researcher","last_name":"Okamoto","id":"3337E116-F248-11E8-B48F-1D18A9856A87","first_name":"Yuji"},{"orcid":"0000-0001-9735-5315","first_name":"Walter","last_name":"Kaufmann","id":"3F99E422-F248-11E8-B48F-1D18A9856A87","contributor_type":"researcher"},{"first_name":"Nils ","contributor_type":"researcher","last_name":"Brose"},{"first_name":"Ryuichi","contributor_type":"researcher","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","last_name":"Shigemoto","orcid":"0000-0001-8761-9444"},{"orcid":"0000-0001-5001-4804","first_name":"Peter M","last_name":"Jonas","id":"353C1B58-F248-11E8-B48F-1D18A9856A87","contributor_type":"supervisor"}],"author":[{"first_name":"Olena","id":"3F8ABDDA-F248-11E8-B48F-1D18A9856A87","last_name":"Kim","full_name":"Kim, Olena","orcid":"0000-0003-2344-1039"}],"abstract":[{"text":"It is widely believed that information storage in neuronal circuits involves nanoscopic structural changes at synapses, resulting in the formation of synaptic engrams. However, direct evidence for this hypothesis is lacking. To test this conjecture, we combined chemical potentiation, functional analysis by paired pre-postsynaptic recordings, and structural analysis by electron microscopy (EM) and freeze-fracture replica labeling (FRL) at the murine hippocampal mossy fiber synapse, a key synapse in the trisynaptic circuit of the hippocampus. Biophysical analysis of synaptic transmission revealed that forskolin-induced chemical potentiation increased the readily releasable vesicle pool size and vesicular release probability by 146% and 49%, respectively. Structural analysis of mossy fiber synapses by EM and FRL demonstrated an increase in the number of vesicles close to the plasma membrane and the number of clusters of the priming protein Munc13-1, indicating an increase in the number of both docked and primed vesicles. Furthermore, FRL analysis revealed a significant reduction of the distance between Munc13-1 and CaV2.1 Ca2+ channels, suggesting reconfiguration of the channel-vesicle coupling nanotopography. Our results indicate that presynaptic plasticity is associated with structural reorganization of active zones. We propose that changes in potential nanoscopic organization at synaptic vesicle release sites may be correlates of learning and memory at a plastic central synapse.","lang":"eng"}]},{"publication_status":"published","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","publication":"Neurology, Neuroimmunology & Neuroinflammation","language":[{"iso":"eng"}],"related_material":{"link":[{"url":"https://doi.org/10.1101/2023.10.04.560631","relation":"earlier_version"}]},"dataavailabilitystatement":"Data that support the findings of this study are available from the corresponding author on reasonable request.","type":"journal_article","publisher":"Wolters Kluwer","month":"09","ddc":["570"],"oa_version":"Published Version","_id":"17457","scopus_import":"1","isi":1,"DOAJ_listed":"1","page":"e200284","date_published":"2024-09-01T00:00:00Z","has_accepted_license":"1","das_tickbox":"1","pmid":1,"file_date_updated":"2025-01-09T13:42:42Z","issue":"5","status":"public","quality_controlled":"1","acknowledged_ssus":[{"_id":"Bio"},{"_id":"EM-Fac"}],"file":[{"date_updated":"2025-01-09T13:42:42Z","creator":"dernst","access_level":"open_access","file_id":"18815","checksum":"1e6d1230e0387f72752e3268f5330c9e","file_size":855818,"file_name":"2024_NeurologyNeuroimmNeuroinflamm_RitzauJost.pdf","success":1,"relation":"main_file","date_created":"2025-01-09T13:42:42Z","content_type":"application/pdf"}],"doi":"10.1212/NXI.0000000000200284","publication_identifier":{"eissn":["2332-7812"]},"fulldoi":"https://doi.org/10.1212/NXI.0000000000200284","OA_type":"gold","OA_place":"publisher","department":[{"_id":"RySh"}],"title":"LGI1 autoantibodies enhance synaptic transmission by presynaptic Kv1 loss and increased action potential broadening","date_updated":"2026-09-17T11:27:41Z","abstract":[{"text":"Autoantibodies against the protein leucine-rich glioma inactivated 1 (LGI1) cause the most\r\ncommon subtype of autoimmune encephalitis with predominant involvement of the limbic\r\nsystem, associated with seizures and memory deficits. LGI1 and its receptor ADAM22 are part\r\nof a transsynaptic protein complex that includes several proteins involved in presynaptic\r\nneurotransmitter release and postsynaptic glutamate sensing. Autoantibodies against LGI1\r\nincrease excitatory synaptic strength, but studies that genetically disrupt the LGI1-ADAM22\r\ncomplex report a reduction in postsynaptic glutamate receptor-mediated responses. Thus, the\r\nmechanisms underlying the increased synaptic strength induced by LGI1 autoantibodies remain elusive, and the contributions of presynaptic molecules to the LGI1-transsynaptic complex remain unclear. We therefore investigated the presynaptic mechanisms that mediate\r\nautoantibody-induced synaptic strengthening.","lang":"eng"}],"author":[{"last_name":"Ritzau-Jost","first_name":"Andreas","full_name":"Ritzau-Jost, Andreas"},{"first_name":"Felix","last_name":"Gsell","full_name":"Gsell, Felix"},{"first_name":"Josefine","last_name":"Sell","full_name":"Sell, Josefine"},{"first_name":"Stefan","last_name":"Sachs","full_name":"Sachs, Stefan"},{"full_name":"Montanaro-Punzengruber, Jacqueline-Claire","last_name":"Montanaro-Punzengruber","id":"3786AB44-F248-11E8-B48F-1D18A9856A87","first_name":"Jacqueline-Claire"},{"first_name":"Toni","last_name":"Kirmann","full_name":"Kirmann, Toni"},{"full_name":"Maaß, Sebastian","first_name":"Sebastian","last_name":"Maaß"},{"full_name":"Irani, Sarosh R.","first_name":"Sarosh R.","last_name":"Irani"},{"first_name":"Christian","last_name":"Werner","full_name":"Werner, Christian"},{"full_name":"Geis, Christian","first_name":"Christian","last_name":"Geis"},{"last_name":"Sauer","first_name":"Markus","full_name":"Sauer, Markus"},{"orcid":"0000-0001-8761-9444","full_name":"Shigemoto, Ryuichi","first_name":"Ryuichi","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","last_name":"Shigemoto"},{"last_name":"Hallermann","first_name":"Stefan","full_name":"Hallermann, Stefan"}],"researchdata_availability":"upon request","day":"01","volume":11,"project":[{"grant_number":"I04638","name":"LGI1 antibody-induced pathophysiology in synapses","_id":"05970B30-7A3F-11EA-A408-12923DDC885E"}],"citation":{"apa":"Ritzau-Jost, A., Gsell, F., Sell, J., Sachs, S., Montanaro-Punzengruber, J.-C., Kirmann, T., … Hallermann, S. (2024). LGI1 autoantibodies enhance synaptic transmission by presynaptic Kv1 loss and increased action potential broadening. <i>Neurology, Neuroimmunology &#38; Neuroinflammation</i>. Wolters Kluwer. <a href=\"https://doi.org/10.1212/NXI.0000000000200284\">https://doi.org/10.1212/NXI.0000000000200284</a>","ieee":"A. Ritzau-Jost <i>et al.</i>, “LGI1 autoantibodies enhance synaptic transmission by presynaptic Kv1 loss and increased action potential broadening,” <i>Neurology, Neuroimmunology &#38; Neuroinflammation</i>, vol. 11, no. 5. Wolters Kluwer, p. e200284, 2024.","ista":"Ritzau-Jost A, Gsell F, Sell J, Sachs S, Montanaro-Punzengruber J-C, Kirmann T, Maaß S, Irani SR, Werner C, Geis C, Sauer M, Shigemoto R, Hallermann S. 2024. LGI1 autoantibodies enhance synaptic transmission by presynaptic Kv1 loss and increased action potential broadening. Neurology, Neuroimmunology &#38; Neuroinflammation. 11(5), e200284.","chicago":"Ritzau-Jost, Andreas, Felix Gsell, Josefine Sell, Stefan Sachs, Jacqueline-Claire Montanaro-Punzengruber, Toni Kirmann, Sebastian Maaß, et al. “LGI1 Autoantibodies Enhance Synaptic Transmission by Presynaptic Kv1 Loss and Increased Action Potential Broadening.” <i>Neurology, Neuroimmunology &#38; Neuroinflammation</i>. Wolters Kluwer, 2024. <a href=\"https://doi.org/10.1212/NXI.0000000000200284\">https://doi.org/10.1212/NXI.0000000000200284</a>.","mla":"Ritzau-Jost, Andreas, et al. “LGI1 Autoantibodies Enhance Synaptic Transmission by Presynaptic Kv1 Loss and Increased Action Potential Broadening.” <i>Neurology, Neuroimmunology &#38; Neuroinflammation</i>, vol. 11, no. 5, Wolters Kluwer, 2024, p. e200284, doi:<a href=\"https://doi.org/10.1212/NXI.0000000000200284\">10.1212/NXI.0000000000200284</a>.","short":"A. Ritzau-Jost, F. Gsell, J. Sell, S. Sachs, J.-C. Montanaro-Punzengruber, T. Kirmann, S. Maaß, S.R. Irani, C. Werner, C. Geis, M. Sauer, R. Shigemoto, S. Hallermann, Neurology, Neuroimmunology &#38; Neuroinflammation 11 (2024) e200284.","ama":"Ritzau-Jost A, Gsell F, Sell J, et al. LGI1 autoantibodies enhance synaptic transmission by presynaptic Kv1 loss and increased action potential broadening. <i>Neurology, Neuroimmunology &#38; Neuroinflammation</i>. 2024;11(5):e200284. doi:<a href=\"https://doi.org/10.1212/NXI.0000000000200284\">10.1212/NXI.0000000000200284</a>"},"intvolume":"        11","acknowledgement":"The authors thank Claudia Sommer for expert technical assistance, the Electron Microscopy Facility of IST-Austria for resources, and Tereza Belinova in the Imaging and Optics Facility of IST-Austria for 3D reconstruction. ","external_id":{"isi":["001291908600001"],"pmid":["39141878"]},"oa":1,"article_type":"original","supplementarymaterial":"yes","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)"},"article_processing_charge":"Yes","year":"2024","date_created":"2024-08-25T22:01:07Z"},{"editor":[{"full_name":"Lübke, Joachim H.R. ","last_name":"Lübke","first_name":"Joachim H.R. "},{"full_name":"Rollenhagen, Astrid","first_name":"Astrid","last_name":"Rollenhagen"}],"publisher":"Springer Nature","type":"book_chapter","language":[{"iso":"eng"}],"publication":"New Aspects in Analyzing the Synaptic Organization of the Brain","publication_status":"published","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","page":"123-137","month":"08","scopus_import":"1","_id":"18052","oa_version":"None","status":"public","das_tickbox":"0","place":"New York","date_published":"2024-08-27T00:00:00Z","fulldoi":"https://doi.org/10.1007/978-1-0716-4019-7_8","ec_funded":1,"department":[{"_id":"EM-Fac"},{"_id":"RySh"}],"corr_author":"1","quality_controlled":"1","acknowledged_ssus":[{"_id":"EM-Fac"}],"edition":"1","publication_identifier":{"eisbn":["9781071640197"],"issn":["0893-2336"],"eissn":["1940-6045"],"isbn":["9781071640180"]},"doi":"10.1007/978-1-0716-4019-7_8","author":[{"first_name":"David","last_name":"Kleindienst","id":"42E121A4-F248-11E8-B48F-1D18A9856A87","full_name":"Kleindienst, David"},{"orcid":"0000-0001-9732-3815","full_name":"Costanzo, Tommaso","first_name":"Tommaso","id":"D93824F4-D9BA-11E9-BB12-F207E6697425","last_name":"Costanzo"},{"orcid":"0000-0001-8761-9444","full_name":"Shigemoto, Ryuichi","first_name":"Ryuichi","last_name":"Shigemoto","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87"}],"abstract":[{"text":"Sodium dodecyl sulfate-digested freeze-fracture replica labeling (SDS-FRL) is an electron microscope (EM) sample preparation technique which allows for high-resolution visualization of membrane proteins with high sensitivity. However, image acquisition of specific replica profiles such as synapses in a large field of EM view needs a valid experience and a long time for manual searching. Here, we describe how to utilize deep learning for automatizing image acquisition of specific profiles of interest in replica samples. This protocol facilitates the labor-intensive collection of EM images, in particular for rare profiles. We provide instructions for using SerialEM image acquisition software in conjunction with object detection by our newly developed deep learning software DarEM, to automatically acquire tilt series of all synapses in a selected region. We then show how to perform a mostly automated analysis of gold particle labeling in the acquired images by utilizing Darea software.","lang":"eng"}],"title":"Automated Imaging and Analysis of Synapses in Freeze-Fracture Replica Samples with Deep Learning","date_updated":"2026-10-01T11:17:28Z","day":"27","alternative_title":["Neuromethods"],"citation":{"apa":"Kleindienst, D., Costanzo, T., &#38; Shigemoto, R. (2024). Automated Imaging and Analysis of Synapses in Freeze-Fracture Replica Samples with Deep Learning. In J. H. R. Lübke &#38; A. Rollenhagen (Eds.), <i>New Aspects in Analyzing the Synaptic Organization of the Brain</i> (1st ed., pp. 123–137). New York: Springer Nature. <a href=\"https://doi.org/10.1007/978-1-0716-4019-7_8\">https://doi.org/10.1007/978-1-0716-4019-7_8</a>","ieee":"D. Kleindienst, T. Costanzo, and R. Shigemoto, “Automated Imaging and Analysis of Synapses in Freeze-Fracture Replica Samples with Deep Learning,” in <i>New Aspects in Analyzing the Synaptic Organization of the Brain</i>, 1st ed., J. H. R. Lübke and A. Rollenhagen, Eds. New York: Springer Nature, 2024, pp. 123–137.","ista":"Kleindienst D, Costanzo T, Shigemoto R. 2024.Automated Imaging and Analysis of Synapses in Freeze-Fracture Replica Samples with Deep Learning. In: New Aspects in Analyzing the Synaptic Organization of the Brain. Neuromethods, , 123–137.","chicago":"Kleindienst, David, Tommaso Costanzo, and Ryuichi Shigemoto. “Automated Imaging and Analysis of Synapses in Freeze-Fracture Replica Samples with Deep Learning.” In <i>New Aspects in Analyzing the Synaptic Organization of the Brain</i>, edited by Joachim H.R.  Lübke and Astrid Rollenhagen, 1st ed., 123–37. New York: Springer Nature, 2024. <a href=\"https://doi.org/10.1007/978-1-0716-4019-7_8\">https://doi.org/10.1007/978-1-0716-4019-7_8</a>.","mla":"Kleindienst, David, et al. “Automated Imaging and Analysis of Synapses in Freeze-Fracture Replica Samples with Deep Learning.” <i>New Aspects in Analyzing the Synaptic Organization of the Brain</i>, edited by Joachim H.R.  Lübke and Astrid Rollenhagen, 1st ed., Springer Nature, 2024, pp. 123–37, doi:<a href=\"https://doi.org/10.1007/978-1-0716-4019-7_8\">10.1007/978-1-0716-4019-7_8</a>.","short":"D. Kleindienst, T. Costanzo, R. Shigemoto, in:, J.H.R. Lübke, A. Rollenhagen (Eds.), New Aspects in Analyzing the Synaptic Organization of the Brain, 1st ed., Springer Nature, New York, 2024, pp. 123–137.","ama":"Kleindienst D, Costanzo T, Shigemoto R. Automated Imaging and Analysis of Synapses in Freeze-Fracture Replica Samples with Deep Learning. In: Lübke JHR, Rollenhagen A, eds. <i>New Aspects in Analyzing the Synaptic Organization of the Brain</i>. 1st ed. New York: Springer Nature; 2024:123-137. doi:<a href=\"https://doi.org/10.1007/978-1-0716-4019-7_8\">10.1007/978-1-0716-4019-7_8</a>"},"project":[{"grant_number":"694539","_id":"25CA28EA-B435-11E9-9278-68D0E5697425","name":"In situ analysis of single channel subunit composition in neurons: physiological implication in synaptic plasticity and behaviour","call_identifier":"H2020"}],"researchdata_availability":"no","supplementarymaterial":"no","acknowledgement":"This research was supported by the European Research Council Advanced Grant 694539 to RS and by the Scientific Service Units of IST Austria through resources provided by the Electron Microscopy Facility.","article_processing_charge":"No","date_created":"2024-09-10T12:32:38Z","year":"2024"},{"isi":1,"_id":"18445","scopus_import":"1","oa_version":"Published Version","month":"10","ddc":["570"],"PlanS_conform":"1","DOAJ_listed":"1","related_material":{"record":[{"status":"public","relation":"research_data","id":"22961"}]},"language":[{"iso":"eng"}],"publication":"Nature Communications","publication_status":"published","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","publisher":"Springer Nature","type":"journal_article","dataavailabilitystatement":"The snRNA-seq data generated in this study have been deposited in the NCBI Gene Expression Omnibus database under accession code GSE132730 and as ‘Supplementary Data 1 - Neuro2a-onecut3-overexpression’. All other primary data were made publically available at https://github.com/Harkany-Lab/Zupancic_2023 and deposited to Figshare.com with https://doi.org/10.6084/m9.figshare.22680433. Source data are provided with this paper.","publication_identifier":{"eissn":["2041-1723"]},"doi":"10.1038/s41467-024-52762-z","file":[{"date_created":"2024-10-21T12:15:38Z","content_type":"application/pdf","success":1,"relation":"main_file","checksum":"03d6dd1b84efa24e9e9ede748d08764d","file_size":7215329,"file_name":"2024_NatureComm_Zupancic.pdf","access_level":"open_access","date_updated":"2024-10-21T12:15:38Z","creator":"dernst","file_id":"18460"}],"quality_controlled":"1","department":[{"_id":"RySh"}],"OA_place":"publisher","OA_type":"gold","fulldoi":"https://doi.org/10.1038/s41467-024-52762-z","has_accepted_license":"1","das_tickbox":"1","date_published":"2024-10-05T00:00:00Z","status":"public","file_date_updated":"2024-10-21T12:15:38Z","pmid":1,"article_number":"8631","researchdata_availability":"yes","intvolume":"        15","citation":{"ista":"Zupančič M, Keimpema E, Tretiakov EO, Eder SJ, Lev I, Englmaier L, Bhandari P, Fietz SA, Härtig W, Renaux E, Villunger A, Hökfelt T, Zimmer M, Clotman F, Harkany T. 2024. Concerted transcriptional regulation of the morphogenesis of hypothalamic neurons by ONECUT3. Nature Communications. 15, 8631.","ieee":"M. Zupančič <i>et al.</i>, “Concerted transcriptional regulation of the morphogenesis of hypothalamic neurons by ONECUT3,” <i>Nature Communications</i>, vol. 15. Springer Nature, 2024.","apa":"Zupančič, M., Keimpema, E., Tretiakov, E. O., Eder, S. J., Lev, I., Englmaier, L., … Harkany, T. (2024). Concerted transcriptional regulation of the morphogenesis of hypothalamic neurons by ONECUT3. <i>Nature Communications</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41467-024-52762-z\">https://doi.org/10.1038/s41467-024-52762-z</a>","mla":"Zupančič, Maja, et al. “Concerted Transcriptional Regulation of the Morphogenesis of Hypothalamic Neurons by ONECUT3.” <i>Nature Communications</i>, vol. 15, 8631, Springer Nature, 2024, doi:<a href=\"https://doi.org/10.1038/s41467-024-52762-z\">10.1038/s41467-024-52762-z</a>.","short":"M. Zupančič, E. Keimpema, E.O. Tretiakov, S.J. Eder, I. Lev, L. Englmaier, P. Bhandari, S.A. Fietz, W. Härtig, E. Renaux, A. Villunger, T. Hökfelt, M. Zimmer, F. Clotman, T. Harkany, Nature Communications 15 (2024).","chicago":"Zupančič, Maja, Erik Keimpema, Evgenii O. Tretiakov, Stephanie J. Eder, Itamar Lev, Lukas Englmaier, Pradeep Bhandari, et al. “Concerted Transcriptional Regulation of the Morphogenesis of Hypothalamic Neurons by ONECUT3.” <i>Nature Communications</i>. Springer Nature, 2024. <a href=\"https://doi.org/10.1038/s41467-024-52762-z\">https://doi.org/10.1038/s41467-024-52762-z</a>.","ama":"Zupančič M, Keimpema E, Tretiakov EO, et al. Concerted transcriptional regulation of the morphogenesis of hypothalamic neurons by ONECUT3. <i>Nature Communications</i>. 2024;15. doi:<a href=\"https://doi.org/10.1038/s41467-024-52762-z\">10.1038/s41467-024-52762-z</a>"},"volume":15,"day":"05","date_updated":"2026-10-01T12:17:25Z","title":"Concerted transcriptional regulation of the morphogenesis of hypothalamic neurons by ONECUT3","author":[{"full_name":"Zupančič, Maja","last_name":"Zupančič","first_name":"Maja"},{"full_name":"Keimpema, Erik","first_name":"Erik","last_name":"Keimpema"},{"full_name":"Tretiakov, Evgenii O.","first_name":"Evgenii O.","last_name":"Tretiakov"},{"full_name":"Eder, Stephanie J.","last_name":"Eder","first_name":"Stephanie J."},{"full_name":"Lev, Itamar","first_name":"Itamar","last_name":"Lev"},{"last_name":"Englmaier","first_name":"Lukas","full_name":"Englmaier, Lukas"},{"first_name":"Pradeep","id":"45EDD1BC-F248-11E8-B48F-1D18A9856A87","last_name":"Bhandari","full_name":"Bhandari, Pradeep","orcid":"0000-0003-0863-4481"},{"full_name":"Fietz, Simone A.","first_name":"Simone A.","last_name":"Fietz"},{"last_name":"Härtig","first_name":"Wolfgang","full_name":"Härtig, Wolfgang"},{"full_name":"Renaux, Estelle","last_name":"Renaux","first_name":"Estelle"},{"full_name":"Villunger, Andreas","first_name":"Andreas","last_name":"Villunger"},{"last_name":"Hökfelt","first_name":"Tomas","full_name":"Hökfelt, Tomas"},{"last_name":"Zimmer","first_name":"Manuel","full_name":"Zimmer, Manuel"},{"full_name":"Clotman, Frédéric","first_name":"Frédéric","last_name":"Clotman"},{"full_name":"Harkany, Tibor","first_name":"Tibor","last_name":"Harkany"}],"abstract":[{"text":"Acquisition of specialized cellular features is controlled by the ordered expression of transcription factors (TFs) along differentiation trajectories. Here, we find a member of the Onecut TF family, ONECUT3, expressed in postmitotic neurons that leave their Ascl1+/Onecut1/2+ proliferative domain in the vertebrate hypothalamus to instruct neuronal differentiation. We combined single-cell RNA-seq and gain-of-function experiments for gene network reconstruction to show that ONECUT3 affects the polarization and morphogenesis of both hypothalamic GABA-derived dopamine and thyrotropin-releasing hormone (TRH)+ glutamate neurons through neuron navigator-2 (NAV2). In vivo, siRNA-mediated knockdown of ONECUT3 in neonatal mice reduced NAV2 mRNA, as well as neurite complexity in Onecut3-containing neurons, while genetic deletion of Onecut3/ceh-48 in C. elegans impaired neurocircuit wiring, and sensory discrimination-based behaviors. Thus, ONECUT3, conserved across neuronal subtypes and many species, underpins the polarization and morphological plasticity of phenotypically distinct neurons that descend from a common pool of Ascl1+ progenitors in the hypothalamus.","lang":"eng"}],"year":"2024","date_created":"2024-10-20T22:02:05Z","article_processing_charge":"Yes (via OA deal)","oa":1,"external_id":{"pmid":["39366958"],"isi":["001409493300014"]},"acknowledgement":"The authors thank Z. Máté, G. Szabó, and F. Erdélyi for the custom generation of transgenic mouse lines, C. Fekete for Trh transgenic tissues (all from the Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary), A. Goudmaeker for IVF recovery of a frozen mouse line (SSS animal facility, Université catholique de Louvain), and Y. Yanagawa (Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan) for providing GAD67gfp/+ mice. We also thank S. Cloer, D. Preininger, and A. Weissenbacher (Tiergarten Schönbrunn, Vienna, Austria) for providing naked mole rats, Seba’s fruit bats, and Indian flying foxes, as well as F. Aujard (CNRS, UMR 7179 ‘Adaptive mechanisms and evolution’, France) for Microcebus tissues. I. Milenkovic and G.G. Kovács (Clinical Institute of Neurology, Medical University of Vienna, Vienna, Austria) are acknowledged for providing post-mortem human brain samples. We are indebted to S. Rehman (Medical University of Vienna), M. Kalusa (University of Leipzig, Leipzig, Germany), and W. Reimann (Paul Flechsig Institute for Brain Research, Leipzig, Germany) for their technical assistance. C. elegans strains were provided by the National Bioresource Project for the nematode, Japan, and the CGC, with the latter being funded by the NIH Office of Research Infrastructure Programs (P40 OD010440). This work was supported by the Austrian Science Fund (FWF, P 34121-B; to E.K.), the Swedish Research Council (2023-03058, T.Ha; 2020-01688, T.Hö.), the Swedish Brain Foundation (Hjärnfonden, FO2022-0300, to T.Ha.), the Novo Nordisk Foundation (NNF23OC0084476, to T.Ha.), the European Research Council (FOODFORLIFE, ERC-2020-AdG-101021016; to T.Ha.), the Université Catholique de Louvain (‘Fonds spéciaux de recherche’-FSR, to F.C.), and Fonds de la Recherche Scientifique F.R.S.-FNRS (‘Project de recherche (PDR)’ #T.0039.21, to F.C.). S.J.E. is supported by the Simons Foundation #543069. I.L. is supported by a post-doctoral fellowship from the Human Frontiers Science Program (LT000335/2020-L). E.R. holds a PhD grant from the FRIA (F.R.S.-FNRS, Belgium). F.C. is a Research Director of the F.R.S.-FNRS (Belgium).\r\nOpen access funding provided by Karolinska Institute.","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)"},"supplementarymaterial":"yes","article_type":"original"},{"acknowledgement":"We thank J. Vorlaufer, N. Agudelo-Dueñas, W. Jahr and A. Wartak for microscope maintenance and troubleshooting; C. Kreuzinger, A. Freeman and I. Erber for technical assistance; and M. Tomschik for support with obtaining human samples. We gratefully acknowledge E. Miguel for setting up webKnossos and M. Šuplata for computational support and hardware control. We are grateful to R. Shigemoto and B. Bickel for generous support and M. Sixt and S. Boyd (Stanford University) for discussions and critical reading of the paper. PSD95-HaloTag mice were kindly provided by S. Grant (University of Edinburgh). We acknowledge expert support by Institute of Science and Technology Austria’s scientific computing, imaging and optics, preclinical and lab support facilities and by the Miba machine shop and library. We gratefully acknowledge funding by the following sources: Austrian Science Fund (FWF) grant I3600-B27 (J.G.D.); Austrian Science Fund (FWF) grant DK W1232 (J.G.D. and J.M.M.); Austrian Science Fund (FWF) grant Z 312-B27, Wittgenstein award (P.J.); Austrian Science Fund (FWF) projects I4685-B, I6565-B (SYNABS) and DOC 33-B27 (R.H.); Gesellschaft für Forschungsförderung NÖ (NFB) grant LSC18-022 (J.G.D.); European Union’s Horizon 2020 research and innovation programme, European Research Council (ERC) grant 715508 – REVERSEAUTISM (G.N.); European Union’s Horizon 2020 research and innovation programme, European Research Council (ERC) grant 692692 – GIANTSYN (P.J.); Marie Skłodowska-Curie Actions Fellowship GA no. 665385 under the EU Horizon 2020 program (J.M.M. and J.L.); and Marie Skłodowska-Curie Actions Individual Fellowship no. 101026635 under the EU Horizon 2020 program (J.F.W.).","external_id":{"isi":["001065254200001"],"pmid":["37653226"]},"oa":1,"article_type":"original","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)"},"article_processing_charge":"Yes (in subscription journal)","year":"2024","date_created":"2023-09-03T22:01:15Z","title":"Imaging brain tissue architecture across millimeter to nanometer scales","date_updated":"2026-10-02T11:27:12Z","author":[{"id":"443DB6DE-F248-11E8-B48F-1D18A9856A87","last_name":"Michalska","first_name":"Julia M","full_name":"Michalska, Julia M","orcid":"0000-0003-3862-1235"},{"first_name":"Julia","id":"46E28B80-F248-11E8-B48F-1D18A9856A87","last_name":"Lyudchik","full_name":"Lyudchik, Julia"},{"full_name":"Velicky, Philipp","orcid":"0000-0002-2340-7431","id":"39BDC62C-F248-11E8-B48F-1D18A9856A87","last_name":"Velicky","first_name":"Philipp"},{"full_name":"Korinkova, Hana","first_name":"Hana","id":"ee3cb6ca-ec98-11ea-ae11-ff703e2254ed","last_name":"Korinkova"},{"full_name":"Watson, Jake","orcid":"0000-0002-8698-3823","first_name":"Jake","id":"63836096-4690-11EA-BD4E-32803DDC885E","last_name":"Watson"},{"first_name":"Alban","last_name":"Cenameri","id":"9ac8f577-2357-11eb-997a-e566c5550886","full_name":"Cenameri, Alban"},{"first_name":"Christoph M","last_name":"Sommer","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-1216-9105","full_name":"Sommer, Christoph M"},{"first_name":"Nicole","id":"4CD6AAC6-F248-11E8-B48F-1D18A9856A87","last_name":"Amberg","full_name":"Amberg, Nicole","orcid":"0000-0002-3183-8207"},{"id":"41CB84B2-F248-11E8-B48F-1D18A9856A87","last_name":"Venturino","first_name":"Alessandro","orcid":"0000-0003-2356-9403","full_name":"Venturino, Alessandro"},{"last_name":"Roessler","first_name":"Karl","full_name":"Roessler, Karl"},{"first_name":"Thomas","last_name":"Czech","full_name":"Czech, Thomas"},{"first_name":"Romana","last_name":"Höftberger","full_name":"Höftberger, Romana"},{"first_name":"Sandra","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","last_name":"Siegert","full_name":"Siegert, Sandra","orcid":"0000-0001-8635-0877"},{"last_name":"Novarino","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","first_name":"Gaia","orcid":"0000-0002-7673-7178","full_name":"Novarino, Gaia"},{"orcid":"0000-0001-5001-4804","full_name":"Jonas, Peter M","first_name":"Peter M","id":"353C1B58-F248-11E8-B48F-1D18A9856A87","last_name":"Jonas"},{"id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","last_name":"Danzl","first_name":"Johann G","orcid":"0000-0001-8559-3973","full_name":"Danzl, Johann G"}],"abstract":[{"lang":"eng","text":"Mapping the complex and dense arrangement of cells and their connectivity in brain tissue demands nanoscale spatial resolution imaging. Super-resolution optical microscopy excels at visualizing specific molecules and individual cells but fails to provide tissue context. Here we developed Comprehensive Analysis of Tissues across Scales (CATS), a technology to densely map brain tissue architecture from millimeter regional to nanometer synaptic scales in diverse chemically fixed brain preparations, including rodent and human. CATS uses fixation-compatible extracellular labeling and optical imaging, including stimulated emission depletion or expansion microscopy, to comprehensively delineate cellular structures. It enables three-dimensional reconstruction of single synapses and mapping of synaptic connectivity by identification and analysis of putative synaptic cleft regions. Applying CATS to the mouse hippocampal mossy fiber circuitry, we reconstructed and quantified the synaptic input and output structure of identified neurons. We furthermore demonstrate applicability to clinically derived human tissue samples, including formalin-fixed paraffin-embedded routine diagnostic specimens, for visualizing the cellular architecture of brain tissue in health and disease."}],"day":"01","volume":42,"project":[{"grant_number":"I03600","name":"Optical control of synaptic function via adhesion molecules","_id":"265CB4D0-B435-11E9-9278-68D0E5697425","call_identifier":"FWF"},{"call_identifier":"FWF","_id":"2548AE96-B435-11E9-9278-68D0E5697425","name":"Molecular Drug Targets","grant_number":"W1232"},{"grant_number":"Z00312","name":"Synaptic communication in neuronal microcircuits","_id":"25C5A090-B435-11E9-9278-68D0E5697425","call_identifier":"FWF"},{"grant_number":"LS18-022","name":"High content imaging to decode human immune cell interactions in health and allergic disease","_id":"23889792-32DE-11EA-91FC-C7463DDC885E"},{"name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models","_id":"25444568-B435-11E9-9278-68D0E5697425","grant_number":"715508","call_identifier":"H2020"},{"name":"Biophysics and circuit function of a giant cortical glutamatergic synapse","_id":"25B7EB9E-B435-11E9-9278-68D0E5697425","grant_number":"692692","call_identifier":"H2020"},{"call_identifier":"H2020","name":"International IST Doctoral Program","_id":"2564DBCA-B435-11E9-9278-68D0E5697425","grant_number":"665385"},{"call_identifier":"H2020","grant_number":"101026635","name":"Synaptic computations of the hippocampal CA3 circuitry","_id":"fc2be41b-9c52-11eb-aca3-faa90aa144e9"}],"citation":{"ama":"Michalska JM, Lyudchik J, Velicky P, et al. Imaging brain tissue architecture across millimeter to nanometer scales. <i>Nature Biotechnology</i>. 2024;42:1051-1064. doi:<a href=\"https://doi.org/10.1038/s41587-023-01911-8\">10.1038/s41587-023-01911-8</a>","apa":"Michalska, J. M., Lyudchik, J., Velicky, P., Korinkova, H., Watson, J., Cenameri, A., … Danzl, J. G. (2024). Imaging brain tissue architecture across millimeter to nanometer scales. <i>Nature Biotechnology</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41587-023-01911-8\">https://doi.org/10.1038/s41587-023-01911-8</a>","ieee":"J. M. Michalska <i>et al.</i>, “Imaging brain tissue architecture across millimeter to nanometer scales,” <i>Nature Biotechnology</i>, vol. 42. Springer Nature, pp. 1051–1064, 2024.","ista":"Michalska JM, Lyudchik J, Velicky P, Korinkova H, Watson J, Cenameri A, Sommer CM, Amberg N, Venturino A, Roessler K, Czech T, Höftberger R, Siegert S, Novarino G, Jonas PM, Danzl JG. 2024. Imaging brain tissue architecture across millimeter to nanometer scales. Nature Biotechnology. 42, 1051–1064.","chicago":"Michalska, Julia M, Julia Lyudchik, Philipp Velicky, Hana Korinkova, Jake Watson, Alban Cenameri, Christoph M Sommer, et al. “Imaging Brain Tissue Architecture across Millimeter to Nanometer Scales.” <i>Nature Biotechnology</i>. Springer Nature, 2024. <a href=\"https://doi.org/10.1038/s41587-023-01911-8\">https://doi.org/10.1038/s41587-023-01911-8</a>.","mla":"Michalska, Julia M., et al. “Imaging Brain Tissue Architecture across Millimeter to Nanometer Scales.” <i>Nature Biotechnology</i>, vol. 42, Springer Nature, 2024, pp. 1051–64, doi:<a href=\"https://doi.org/10.1038/s41587-023-01911-8\">10.1038/s41587-023-01911-8</a>.","short":"J.M. Michalska, J. Lyudchik, P. Velicky, H. Korinkova, J. Watson, A. Cenameri, C.M. Sommer, N. Amberg, A. Venturino, K. Roessler, T. Czech, R. Höftberger, S. Siegert, G. Novarino, P.M. Jonas, J.G. Danzl, Nature Biotechnology 42 (2024) 1051–1064."},"intvolume":"        42","date_published":"2024-07-01T00:00:00Z","has_accepted_license":"1","pmid":1,"file_date_updated":"2025-01-09T07:48:01Z","status":"public","quality_controlled":"1","acknowledged_ssus":[{"_id":"ScienComp"},{"_id":"Bio"},{"_id":"PreCl"},{"_id":"LifeSc"},{"_id":"M-Shop"},{"_id":"E-Lib"}],"corr_author":"1","file":[{"content_type":"application/pdf","date_created":"2025-01-09T07:48:01Z","relation":"main_file","success":1,"file_name":"2024_NatureBiotech_Michalska.pdf","file_size":26065165,"checksum":"57d5fafb16f02dcb9f7dddb1bd7e2a71","file_id":"18784","access_level":"open_access","creator":"dernst","date_updated":"2025-01-09T07:48:01Z"}],"doi":"10.1038/s41587-023-01911-8","publication_identifier":{"eissn":["1546-1696"],"issn":["1087-0156"]},"OA_type":"hybrid","fulldoi":"https://doi.org/10.1038/s41587-023-01911-8","department":[{"_id":"SaSi"},{"_id":"GaNo"},{"_id":"PeJo"},{"_id":"JoDa"},{"_id":"Bio"},{"_id":"RySh"}],"OA_place":"publisher","ec_funded":1,"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publication_status":"published","language":[{"iso":"eng"}],"publication":"Nature Biotechnology","related_material":{"link":[{"relation":"software","url":"https://github.com/danzllab/CATS"}],"record":[{"status":"deleted","id":"18660","relation":"dissertation_contains"},{"relation":"research_data","id":"13126","status":"public"},{"status":"public","relation":"dissertation_contains","id":"18674"}]},"type":"journal_article","publisher":"Springer Nature","month":"07","ddc":["570"],"_id":"14257","scopus_import":"1","oa_version":"Published Version","isi":1,"page":"1051-1064"},{"APC_amount":"5887,8 EUR","tmp":{"name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","image":"/images/cc_by_nc_nd.png","short":"CC BY-NC-ND (4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode"},"article_type":"original","oa":1,"external_id":{"isi":["001208567300006"],"pmid":["38346189"]},"acknowledgement":"We thank Erwin Neher and Ipe Ninan for critical comments on the manuscript. This project has received funding from the European Research Council (ERC) and European Commission, under the European Union’s Horizon 2020 research and innovation program (ERC grant agreement no. 694539 to R.S. and the Marie Skłodowska-Curie grant agreement no. 665385 to C.Ö.). This study was supported by the Cooperative Study Program of Center for Animal Resources and Collaborative Study of NINS. We thank Kohgaku Eguchi for statistical analysis, Yu Kasugai for additional EM imaging, Robert Beattie for the design of the slice recovery chamber for Flash and Freeze experiments, Todor Asenov from the ISTA machine shop for custom part preparations for high-pressure freezing, the ISTA preclinical facility for animal caretaking, and the ISTA EM facilities for technical support.","year":"2024","date_created":"2024-03-05T09:23:55Z","article_processing_charge":"Yes (in subscription journal)","abstract":[{"lang":"eng","text":"GABAB receptor (GBR) activation inhibits neurotransmitter release in axon terminals in the brain, except in medial habenula (MHb) terminals, which show robust potentiation. However, mechanisms underlying this enigmatic potentiation remain elusive. Here, we report that GBR activation on MHb terminals induces an activity-dependent transition from a facilitating, tonic to a depressing, phasic neurotransmitter release mode. This transition is accompanied by a 4.1-fold increase in readily releasable vesicle pool (RRP) size and a 3.5-fold increase of docked synaptic vesicles (SVs) at the presynaptic active zone (AZ). Strikingly, the depressing phasic release exhibits looser coupling distance than the tonic release. Furthermore, the tonic and phasic release are selectively affected by deletion of synaptoporin (SPO) and Ca\r\n            <jats:sup>2+</jats:sup>\r\n            -dependent activator protein for secretion 2 (CAPS2), respectively. SPO modulates augmentation, the short-term plasticity associated with tonic release, and CAPS2 retains the increased RRP for initial responses in phasic response trains. The cytosolic protein CAPS2 showed a SV-associated distribution similar to the vesicular transmembrane protein SPO, and they were colocalized in the same terminals. We developed the “Flash and Freeze-fracture” method, and revealed the release of SPO-associated vesicles in both tonic and phasic modes and activity-dependent recruitment of CAPS2 to the AZ during phasic release, which lasted several minutes. Overall, these results indicate that GBR activation translocates CAPS2 to the AZ along with the fusion of CAPS2-associated SVs, contributing to persistency of the RRP increase. Thus, we identified structural and molecular mechanisms underlying tonic and phasic neurotransmitter release and their transition by GBR activation in MHb terminals."}],"author":[{"orcid":"0000-0002-3509-1948","full_name":"Koppensteiner, Peter","last_name":"Koppensteiner","id":"3B8B25A8-F248-11E8-B48F-1D18A9856A87","first_name":"Peter"},{"first_name":"Pradeep","id":"45EDD1BC-F248-11E8-B48F-1D18A9856A87","last_name":"Bhandari","full_name":"Bhandari, Pradeep","orcid":"0000-0003-0863-4481"},{"first_name":"Hüseyin C","id":"4659D740-F248-11E8-B48F-1D18A9856A87","last_name":"Önal","full_name":"Önal, Hüseyin C","orcid":"0000-0002-2771-2011"},{"orcid":"0000-0003-0005-401X","full_name":"Borges Merjane, Carolina","first_name":"Carolina","id":"4305C450-F248-11E8-B48F-1D18A9856A87","last_name":"Borges Merjane"},{"first_name":"Elodie","id":"3B59276A-F248-11E8-B48F-1D18A9856A87","last_name":"Le Monnier","full_name":"Le Monnier, Elodie"},{"first_name":"Utsa","last_name":"Roy","id":"4d26cf11-5355-11ee-ae5a-eb05e255b9b2","full_name":"Roy, Utsa"},{"last_name":"Nakamura","first_name":"Yukihiro","full_name":"Nakamura, Yukihiro"},{"first_name":"Tetsushi","last_name":"Sadakata","full_name":"Sadakata, Tetsushi"},{"full_name":"Sanbo, Makoto","first_name":"Makoto","last_name":"Sanbo"},{"last_name":"Hirabayashi","first_name":"Masumi","full_name":"Hirabayashi, Masumi"},{"full_name":"Rhee, JeongSeop","first_name":"JeongSeop","last_name":"Rhee"},{"last_name":"Brose","first_name":"Nils","full_name":"Brose, Nils"},{"id":"353C1B58-F248-11E8-B48F-1D18A9856A87","last_name":"Jonas","first_name":"Peter M","full_name":"Jonas, Peter M","orcid":"0000-0001-5001-4804"},{"first_name":"Ryuichi","last_name":"Shigemoto","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","full_name":"Shigemoto, Ryuichi","orcid":"0000-0001-8761-9444"}],"date_updated":"2026-10-14T22:30:36Z","title":"GABAB receptors induce phasic release from medial habenula terminals through activity-dependent recruitment of release-ready vesicles","project":[{"grant_number":"694539","_id":"25CA28EA-B435-11E9-9278-68D0E5697425","name":"In situ analysis of single channel subunit composition in neurons: physiological implication in synaptic plasticity and behaviour","call_identifier":"H2020"},{"name":"International IST Doctoral Program","_id":"2564DBCA-B435-11E9-9278-68D0E5697425","grant_number":"665385","call_identifier":"H2020"}],"citation":{"short":"P. Koppensteiner, P. Bhandari, C. Önal, C. Borges Merjane, E. Le Monnier, U. Roy, Y. Nakamura, T. Sadakata, M. Sanbo, M. Hirabayashi, J. Rhee, N. Brose, P.M. Jonas, R. Shigemoto, Proceedings of the National Academy of Sciences of the United States of America 121 (2024).","mla":"Koppensteiner, Peter, et al. “GABAB Receptors Induce Phasic Release from Medial Habenula Terminals through Activity-Dependent Recruitment of Release-Ready Vesicles.” <i>Proceedings of the National Academy of Sciences of the United States of America</i>, vol. 121, no. 8, e2301449121, National Academy of Sciences, 2024, doi:<a href=\"https://doi.org/10.1073/pnas.2301449121\">10.1073/pnas.2301449121</a>.","chicago":"Koppensteiner, Peter, Pradeep Bhandari, Cihan Önal, Carolina Borges Merjane, Elodie Le Monnier, Utsa Roy, Yukihiro Nakamura, et al. “GABAB Receptors Induce Phasic Release from Medial Habenula Terminals through Activity-Dependent Recruitment of Release-Ready Vesicles.” <i>Proceedings of the National Academy of Sciences of the United States of America</i>. National Academy of Sciences, 2024. <a href=\"https://doi.org/10.1073/pnas.2301449121\">https://doi.org/10.1073/pnas.2301449121</a>.","ista":"Koppensteiner P, Bhandari P, Önal C, Borges Merjane C, Le Monnier E, Roy U, Nakamura Y, Sadakata T, Sanbo M, Hirabayashi M, Rhee J, Brose N, Jonas PM, Shigemoto R. 2024. GABAB receptors induce phasic release from medial habenula terminals through activity-dependent recruitment of release-ready vesicles. Proceedings of the National Academy of Sciences of the United States of America. 121(8), e2301449121.","ieee":"P. Koppensteiner <i>et al.</i>, “GABAB receptors induce phasic release from medial habenula terminals through activity-dependent recruitment of release-ready vesicles,” <i>Proceedings of the National Academy of Sciences of the United States of America</i>, vol. 121, no. 8. National Academy of Sciences, 2024.","apa":"Koppensteiner, P., Bhandari, P., Önal, C., Borges Merjane, C., Le Monnier, E., Roy, U., … Shigemoto, R. (2024). GABAB receptors induce phasic release from medial habenula terminals through activity-dependent recruitment of release-ready vesicles. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. National Academy of Sciences. <a href=\"https://doi.org/10.1073/pnas.2301449121\">https://doi.org/10.1073/pnas.2301449121</a>","ama":"Koppensteiner P, Bhandari P, Önal C, et al. GABAB receptors induce phasic release from medial habenula terminals through activity-dependent recruitment of release-ready vesicles. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. 2024;121(8). doi:<a href=\"https://doi.org/10.1073/pnas.2301449121\">10.1073/pnas.2301449121</a>"},"intvolume":"       121","volume":121,"day":"20","article_number":"e2301449121","status":"public","issue":"8","file_date_updated":"2024-03-12T13:42:42Z","pmid":1,"has_accepted_license":"1","date_published":"2024-02-20T00:00:00Z","OA_place":"publisher","ec_funded":1,"department":[{"_id":"RySh"},{"_id":"PeJo"}],"fulldoi":"https://doi.org/10.1073/pnas.2301449121","OA_type":"hybrid","publication_identifier":{"issn":["0027-8424"],"eissn":["1091-6490"]},"file":[{"date_created":"2024-03-12T13:42:42Z","content_type":"application/pdf","success":1,"relation":"main_file","checksum":"b25b2a057c266ff317a48b0d54d6fc8a","file_size":13648221,"file_name":"2024_PNAS_Koppensteiner.pdf","date_updated":"2024-03-12T13:42:42Z","creator":"dernst","access_level":"open_access","file_id":"15110"}],"doi":"10.1073/pnas.2301449121","corr_author":"1","acknowledged_ssus":[{"_id":"M-Shop"},{"_id":"PreCl"},{"_id":"EM-Fac"}],"quality_controlled":"1","publisher":"National Academy of Sciences","type":"journal_article","related_material":{"link":[{"url":"https://ista.ac.at/en/news/neuronal-insights-flash-and-freeze-fracture/","description":"News on ISTA Website","relation":"press_release"}],"record":[{"relation":"research_data","id":"13173","status":"public"},{"status":"public","id":"19271","relation":"dissertation_contains"}]},"language":[{"iso":"eng"}],"publication":"Proceedings of the National Academy of Sciences of the United States of America","publication_status":"published","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","isi":1,"oa_version":"Published Version","_id":"15084","scopus_import":"1","ddc":["570"],"month":"02"},{"OA_place":"publisher","ec_funded":1,"department":[{"_id":"PeJo"},{"_id":"EM-Fac"},{"_id":"RySh"}],"fulldoi":"https://doi.org/10.1016/j.neuron.2023.12.002","OA_type":"hybrid","file":[{"file_name":"2024_Neuron_Chen.pdf","checksum":"30098b4f0209556ddfb3540a23d07ca5","file_size":8192355,"file_id":"19614","access_level":"open_access","creator":"dernst","date_updated":"2025-04-23T14:02:08Z","content_type":"application/pdf","date_created":"2025-04-23T14:02:08Z","relation":"main_file","success":1}],"doi":"10.1016/j.neuron.2023.12.002","publication_identifier":{"eissn":["1097-4199"],"issn":["0896-6273"]},"corr_author":"1","quality_controlled":"1","acknowledged_ssus":[{"_id":"EM-Fac"},{"_id":"PreCl"},{"_id":"M-Shop"}],"file_date_updated":"2025-04-23T14:02:08Z","status":"public","issue":"5","pmid":1,"has_accepted_license":"1","date_published":"2024-03-06T00:00:00Z","page":"755-771.e9","isi":1,"_id":"14843","scopus_import":"1","oa_version":"Published Version","month":"03","ddc":["570"],"PlanS_conform":"1","publisher":"Elsevier","type":"journal_article","related_material":{"record":[{"id":"15101","relation":"dissertation_contains","status":"public"}],"link":[{"description":"News on ISTA Website","url":"https://ista.ac.at/en/news/synapses-brought-to-the-point/","relation":"press_release"}]},"language":[{"iso":"eng"}],"publication":"Neuron","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publication_status":"published","date_created":"2024-01-21T23:00:56Z","year":"2024","article_processing_charge":"Yes (via OA deal)","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)"},"article_type":"original","oa":1,"external_id":{"isi":["001202925700001"],"pmid":["38215739"]},"acknowledgement":"We thank Drs. David DiGregorio and Erwin Neher for critically reading an earlier version of the manuscript, Ralf Schneggenburger for helpful discussions, Benjamin Suter and Katharina Lichter for support with image analysis, Chris Wojtan for advice on numerical solution of partial differential equations, Maria Reva for help with Ripley analysis, Alois Schlögl for programming, and Akari Hagiwara and Toshihisa Ohtsuka for anti-ELKS antibody. We are grateful to Florian Marr, Christina Altmutter, and Vanessa Zheden for excellent technical assistance and to Eleftheria Kralli-Beller for manuscript editing. This research was supported by the Scientific Services Units (SSUs) of ISTA (Electron Microscopy Facility, Preclinical Facility, and Machine Shop). The project received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 692692), the Fonds zur Förderung der Wissenschaftlichen Forschung (Z 312-B27, Wittgenstein award; P 36232-B), all to P.J., and a DOC fellowship of the Austrian Academy of Sciences to J.-J.C.","intvolume":"       112","project":[{"call_identifier":"H2020","name":"Biophysics and circuit function of a giant cortical glutamatergic synapse","_id":"25B7EB9E-B435-11E9-9278-68D0E5697425","grant_number":"692692"},{"grant_number":"Z00312","name":"Synaptic communication in neuronal microcircuits","_id":"25C5A090-B435-11E9-9278-68D0E5697425","call_identifier":"FWF"},{"grant_number":"P36232","_id":"bd88be38-d553-11ed-ba76-81d5a70a6ef5","name":"Mechanisms of GABA release in hippocampal circuits"},{"_id":"26B66A3E-B435-11E9-9278-68D0E5697425","name":"Development of nanodomain coupling between Ca2+ channels and release sensors at a central inhibitory synapse","grant_number":"25383"}],"citation":{"chicago":"Chen, JingJing, Walter Kaufmann, Chong Chen, itaru Arai, Olena Kim, Ryuichi Shigemoto, and Peter M Jonas. “Developmental Transformation of Ca2+ Channel-Vesicle Nanotopography at a Central GABAergic Synapse.” <i>Neuron</i>. Elsevier, 2024. <a href=\"https://doi.org/10.1016/j.neuron.2023.12.002\">https://doi.org/10.1016/j.neuron.2023.12.002</a>.","mla":"Chen, JingJing, et al. “Developmental Transformation of Ca2+ Channel-Vesicle Nanotopography at a Central GABAergic Synapse.” <i>Neuron</i>, vol. 112, no. 5, Elsevier, 2024, p. 755–771.e9, doi:<a href=\"https://doi.org/10.1016/j.neuron.2023.12.002\">10.1016/j.neuron.2023.12.002</a>.","short":"J. Chen, W. Kaufmann, C. Chen,  itaru Arai, O. Kim, R. Shigemoto, P.M. Jonas, Neuron 112 (2024) 755–771.e9.","apa":"Chen, J., Kaufmann, W., Chen, C., Arai,  itaru, Kim, O., Shigemoto, R., &#38; Jonas, P. M. (2024). Developmental transformation of Ca2+ channel-vesicle nanotopography at a central GABAergic synapse. <i>Neuron</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.neuron.2023.12.002\">https://doi.org/10.1016/j.neuron.2023.12.002</a>","ieee":"J. Chen <i>et al.</i>, “Developmental transformation of Ca2+ channel-vesicle nanotopography at a central GABAergic synapse,” <i>Neuron</i>, vol. 112, no. 5. Elsevier, p. 755–771.e9, 2024.","ista":"Chen J, Kaufmann W, Chen C, Arai  itaru, Kim O, Shigemoto R, Jonas PM. 2024. Developmental transformation of Ca2+ channel-vesicle nanotopography at a central GABAergic synapse. Neuron. 112(5), 755–771.e9.","ama":"Chen J, Kaufmann W, Chen C, et al. Developmental transformation of Ca2+ channel-vesicle nanotopography at a central GABAergic synapse. <i>Neuron</i>. 2024;112(5):755-771.e9. doi:<a href=\"https://doi.org/10.1016/j.neuron.2023.12.002\">10.1016/j.neuron.2023.12.002</a>"},"volume":112,"day":"06","abstract":[{"lang":"eng","text":"The coupling between Ca2+ channels and release sensors is a key factor defining the signaling properties of a synapse. However, the coupling nanotopography at many synapses remains unknown, and it is unclear how it changes during development. To address these questions, we examined coupling at the cerebellar inhibitory basket cell (BC)-Purkinje cell (PC) synapse. Biophysical analysis of transmission by paired recording and intracellular pipette perfusion revealed that the effects of exogenous Ca2+ chelators decreased during development, despite constant reliance of release on P/Q-type Ca2+ channels. Structural analysis by freeze-fracture replica labeling (FRL) and transmission electron microscopy (EM) indicated that presynaptic P/Q-type Ca2+ channels formed nanoclusters throughout development, whereas docked vesicles were only clustered at later developmental stages. Modeling suggested a developmental transformation from a more random to a more clustered coupling nanotopography. Thus, presynaptic signaling developmentally approaches a point-to-point configuration, optimizing speed, reliability, and energy efficiency of synaptic transmission."}],"author":[{"full_name":"Chen, JingJing","first_name":"JingJing","id":"2C4E65C8-F248-11E8-B48F-1D18A9856A87","last_name":"Chen"},{"first_name":"Walter","id":"3F99E422-F248-11E8-B48F-1D18A9856A87","last_name":"Kaufmann","orcid":"0000-0001-9735-5315","full_name":"Kaufmann, Walter"},{"full_name":"Chen, Chong","first_name":"Chong","last_name":"Chen","id":"3DFD581A-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Itaru","id":"32A73F6C-F248-11E8-B48F-1D18A9856A87","last_name":"Arai","full_name":"Arai, Itaru"},{"orcid":"0000-0003-2344-1039","full_name":"Kim, Olena","last_name":"Kim","id":"3F8ABDDA-F248-11E8-B48F-1D18A9856A87","first_name":"Olena"},{"orcid":"0000-0001-8761-9444","full_name":"Shigemoto, Ryuichi","last_name":"Shigemoto","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","first_name":"Ryuichi"},{"first_name":"Peter M","last_name":"Jonas","id":"353C1B58-F248-11E8-B48F-1D18A9856A87","full_name":"Jonas, Peter M","orcid":"0000-0001-5001-4804"}],"date_updated":"2026-10-14T22:31:23Z","title":"Developmental transformation of Ca2+ channel-vesicle nanotopography at a central GABAergic synapse"},{"publisher":"Institute of Science and Technology Austria","type":"research_data","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","related_material":{"link":[{"relation":"research_data","url":"https://pub.ista.ac.at/group_danzl/data/CATS/","description":"Original data for Fig. 5d, Fig. 5d (N2V) and Fig. 5f-i, provided via an external link due to the large size (>10GB) of the datasets. 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Johann G","orcid":"0000-0001-8559-3973","last_name":"Danzl","id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","first_name":"Johann G"}],"abstract":[{"text":"Mapping the complex and dense arrangement of cells and their connectivity in brain tissue demands nanoscale spatial resolution imaging. Super-resolution optical microscopy excels at visualizing specific molecules and individual cells but fails to provide tissue context. Here, we developed Comprehensive Analysis of Tissues across Scales (CATS), a technology to densely map brain tissue architecture from millimeter regional to nanometer synaptic scales in diverse chemically fixed brain preparations, including rodent and human. CATS uses fixation-compatible extracellular labeling and optical imaging, including stimulated emission depletion or expansion microscopy, to comprehensively delineate cellular structures. It enables three-dimensional reconstruction of single synapses and mapping of synaptic connectivity by identification and analysis of putative synaptic cleft regions. Applying CATS to the mouse hippocampal mossy fiber circuitry, we reconstructed and quantified the synaptic input and output structure of identified neurons. We furthermore demonstrate applicability to clinically derived human tissue samples, including formalin-fixed paraffin-embedded routine diagnostic specimens, for visualizing the cellular architecture of brain tissue in health and disease.","lang":"eng"}],"contributor":[{"last_name":"Michalska","id":"443DB6DE-F248-11E8-B48F-1D18A9856A87","first_name":"Julia M"},{"first_name":"Julia","id":"46E28B80-F248-11E8-B48F-1D18A9856A87","last_name":"Lyudchik"},{"id":"39BDC62C-F248-11E8-B48F-1D18A9856A87","last_name":"Velicky","first_name":"Philipp","orcid":"0000-0002-2340-7431"},{"first_name":"Hana","id":"ee3cb6ca-ec98-11ea-ae11-ff703e2254ed","last_name":"Stefanickova"},{"orcid":"0000-0002-8698-3823","first_name":"Jake","id":"63836096-4690-11EA-BD4E-32803DDC885E","last_name":"Watson"},{"first_name":"Alban","id":"9ac8f577-2357-11eb-997a-e566c5550886","last_name":"Cenameri"},{"first_name":"Christoph M","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87","last_name":"Sommer","orcid":"0000-0003-1216-9105"},{"orcid":"0000-0002-3183-8207","first_name":"Nicole","last_name":"Amberg","id":"4CD6AAC6-F248-11E8-B48F-1D18A9856A87"},{"id":"41CB84B2-F248-11E8-B48F-1D18A9856A87","last_name":"Venturino","first_name":"Alessandro","orcid":"0000-0003-2356-9403"},{"last_name":"Roessler","first_name":"Karl"},{"last_name":"Czech","first_name":"Thomas"},{"first_name":"Romana","last_name":"Höftberger"},{"orcid":"0000-0001-8635-0877","first_name":"Sandra","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","last_name":"Siegert"},{"id":"3E57A680-F248-11E8-B48F-1D18A9856A87","last_name":"Novarino","first_name":"Gaia","orcid":"0000-0002-7673-7178"},{"orcid":"0000-0001-5001-4804","first_name":"Peter M","id":"353C1B58-F248-11E8-B48F-1D18A9856A87","last_name":"Jonas"}],"title":"Research data for the publication \"Imaging brain tissue architecture across millimeter to nanometer scales\"","date_updated":"2026-04-14T08:34:35Z","day":"04","project":[{"call_identifier":"FWF","grant_number":"I03600","_id":"265CB4D0-B435-11E9-9278-68D0E5697425","name":"Optical control of synaptic function via adhesion molecules"},{"call_identifier":"FWF","grant_number":"W1232-B24","name":"Molecular Drug Targets","_id":"26AA4EF2-B435-11E9-9278-68D0E5697425"},{"call_identifier":"FWF","grant_number":"Z00312","name":"Synaptic communication in neuronal microcircuits","_id":"25C5A090-B435-11E9-9278-68D0E5697425"},{"_id":"23889792-32DE-11EA-91FC-C7463DDC885E","name":"High content imaging to decode human immune cell interactions in health and allergic disease","grant_number":"LS18-022"},{"call_identifier":"H2020","name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models","_id":"25444568-B435-11E9-9278-68D0E5697425","grant_number":"715508"},{"name":"Biophysics and circuit function of a giant cortical glutamatergic synapse","_id":"25B7EB9E-B435-11E9-9278-68D0E5697425","grant_number":"692692","call_identifier":"H2020"},{"name":"International IST Doctoral Program","_id":"2564DBCA-B435-11E9-9278-68D0E5697425","grant_number":"665385","call_identifier":"H2020"},{"_id":"fc2be41b-9c52-11eb-aca3-faa90aa144e9","name":"Synaptic computations of the hippocampal CA3 circuitry","grant_number":"101026635","call_identifier":"H2020"}],"citation":{"ista":"Danzl JG. 2023. Research data for the publication ‘Imaging brain tissue architecture across millimeter to nanometer scales’, Institute of Science and Technology Austria, <a href=\"https://doi.org/10.15479/AT:ISTA:13126\">10.15479/AT:ISTA:13126</a>.","ieee":"J. G. Danzl, “Research data for the publication ‘Imaging brain tissue architecture across millimeter to nanometer scales.’” Institute of Science and Technology Austria, 2023.","apa":"Danzl, J. G. (2023). Research data for the publication “Imaging brain tissue architecture across millimeter to nanometer scales.” Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:13126\">https://doi.org/10.15479/AT:ISTA:13126</a>","mla":"Danzl, Johann G. <i>Research Data for the Publication “Imaging Brain Tissue Architecture across Millimeter to Nanometer Scales.”</i> Institute of Science and Technology Austria, 2023, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:13126\">10.15479/AT:ISTA:13126</a>.","short":"J.G. Danzl, (2023).","chicago":"Danzl, Johann G. “Research Data for the Publication ‘Imaging Brain Tissue Architecture across Millimeter to Nanometer Scales.’” Institute of Science and Technology Austria, 2023. <a href=\"https://doi.org/10.15479/AT:ISTA:13126\">https://doi.org/10.15479/AT:ISTA:13126</a>.","ama":"Danzl JG. Research data for the publication “Imaging brain tissue architecture across millimeter to nanometer scales.” 2023. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:13126\">10.15479/AT:ISTA:13126</a>"},"tmp":{"image":"/images/cc_by_nc_sa.png","name":"Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-sa/4.0/legalcode","short":"CC BY-NC-SA (4.0)"},"acknowledgement":"We thank Jakob Vorlaufer, Nathalie Agudelo-Dueñas, Wiebke Jahr, Andreas Wartak for microscope maintenance and troubleshooting, Caroline Kreuzinger, Anna Freeman, and Irene Erber for technical assistance and Matthias Tomschik for support with obtaining human samples. We gratefully acknowledge Eder Miguel for setting up webKnossos and Marek Šuplata for computational support and hardware control. We are grateful to Ryuichi Shigemoto and Bernd Bickel for generous support, and Michael Sixt and Scott Boyd (Stanford University) for discussions and critical reading of the manuscript. PSD95-HaloTag mice were kindly provided by Seth Grant (University of Edinburgh). We acknowledge expert support by IST Austria’s scientific computing, imaging and optics, preclinical, and lab support facilities, and by the Library and Miba machine shop.\r\nWe gratefully acknowledge funding by the following sources: \r\nAustrian Science Fund (FWF) grant I3600-B27 (JGD)\r\nAustrian Science Fund (FWF) grant DK W1232 (JGD, JMM)\r\nAustrian Science Fund (FWF) grant Z 312-B27, Wittgenstein award (PJ)\r\nAustrian Science Funds (FWF) projects I4685-B, I6565-B (SYNABS) and DOC 33-B27 (RH)\r\nGesellschaft für Forschungsförderung NÖ (NFB) grant LSC18-022 (JGD)\r\nEuropean Union’s Horizon 2020 research and innovation programme, European Research Council (ERC) grant 715508 – REVERSEAUTISM (GN)\r\nEuropean Union’s Horizon 2020 research and innovation programme, European Research Council (ERC) grant 692692 – GIANTSYN (PJ)\r\nMarie Skłodowska-Curie Actions Fellowship GA no. 665385 under the EU Horizon 2020 program (JMM, JL)\r\nMarie Skłodowska-Curie Actions Individual Fellowship 101026635 under the EU Horizon 2020 program (JFW)","oa":1,"article_processing_charge":"No","date_created":"2023-06-07T07:15:12Z","year":"2023"},{"ddc":["571"],"month":"07","_id":"13173","oa_version":"Published Version","day":"29","citation":{"ista":"Shigemoto R. 2023. Transition from tonic to phasic neurotransmitter release by presynaptic GABAB receptor activation in medial habenula terminals, Institute of Science and Technology Austria, <a href=\"https://doi.org/10.15479/AT:ISTA:13173\">10.15479/AT:ISTA:13173</a>.","apa":"Shigemoto, R. (2023). Transition from tonic to phasic neurotransmitter release by presynaptic GABAB receptor activation in medial habenula terminals. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:13173\">https://doi.org/10.15479/AT:ISTA:13173</a>","ieee":"R. Shigemoto, “Transition from tonic to phasic neurotransmitter release by presynaptic GABAB receptor activation in medial habenula terminals.” Institute of Science and Technology Austria, 2023.","mla":"Shigemoto, Ryuichi. <i>Transition from Tonic to Phasic Neurotransmitter Release by Presynaptic GABAB Receptor Activation in Medial Habenula Terminals</i>. Institute of Science and Technology Austria, 2023, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:13173\">10.15479/AT:ISTA:13173</a>.","short":"R. Shigemoto, (2023).","chicago":"Shigemoto, Ryuichi. “Transition from Tonic to Phasic Neurotransmitter Release by Presynaptic GABAB Receptor Activation in Medial Habenula Terminals.” Institute of Science and Technology Austria, 2023. <a href=\"https://doi.org/10.15479/AT:ISTA:13173\">https://doi.org/10.15479/AT:ISTA:13173</a>.","ama":"Shigemoto R. Transition from tonic to phasic neurotransmitter release by presynaptic GABAB receptor activation in medial habenula terminals. 2023. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:13173\">10.15479/AT:ISTA:13173</a>"},"title":"Transition from tonic to phasic neurotransmitter release by presynaptic GABAB receptor activation in medial habenula terminals","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","date_updated":"2025-09-04T12:16:24Z","related_material":{"record":[{"id":"15084","relation":"used_in_publication","status":"public"}]},"abstract":[{"text":"GABAB receptor (GBR) activation inhibits neurotransmitter release in axon terminals in the brain, except in medial habenula (MHb) terminals, which show robust potentiation. However, mechanisms underlying this enigmatic potentiation remain elusive. Here, we report that GBR activation on MHb terminals induces an activity-dependent transition from a facilitating, tonic to a depressing, phasic neurotransmitter release mode. This transition is accompanied by a 4.1-fold increase in readily releasable vesicle pool (RRP) size and a 3.5-fold increase of docked synaptic vesicles at the presynaptic active zone (AZ). Strikingly, tonic and phasic release exhibit distinct coupling distances and are selectively affected by deletion of synaptoporin (SPO) and Ca2+-dependent activator protein for secretion 2 (CAPS2), respectively. SPO modulates augmentation, the short-term plasticity associated with tonic release, and CAPS2 retains the increased RRP for initial responses in phasic response trains. Double pre-embedding immunolabeling confirmed the co-localization of CAPS2 and SPO inside the same terminal. The cytosolic protein CAPS2 showed a synaptic vesicle (SV)-associated distribution similar to the vesicular transmembrane protein SPO. A newly developed “Flash and Freeze-fracture” method revealed the release of SPO-associated vesicles in both tonic and phasic modes and activity-dependent recruitment of CAPS2 to the AZ during phasic release, which lasted several minutes. Overall, these results indicate that GBR activation translocates CAPS2 to the AZ along with the fusion of CAPS2-associated SVs, contributing to a persistent RRP increase. Thus, we discovered structural and molecular mechanisms underlying tonic and phasic neurotransmitter release and their transition by GBR activation in MHb terminals.","lang":"eng"}],"author":[{"orcid":"0000-0001-8761-9444","full_name":"Shigemoto, Ryuichi","first_name":"Ryuichi","last_name":"Shigemoto","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87"}],"publisher":"Institute of Science and Technology Austria","type":"research_data","corr_author":"1","doi":"10.15479/AT:ISTA:13173","file":[{"relation":"main_file","content_type":"application/x-zip-compressed","date_created":"2023-06-29T13:11:22Z","title":"Outdated Version","file_id":"13174","creator":"shigemot","date_updated":"2023-11-17T14:30:44Z","access_level":"closed","description":"After review an updated version of the data is provided","file_name":"Raw data for Koppensteiner et al.zip","checksum":"ed59170869ba621f89f7c1894092192f","file_size":542873672},{"date_updated":"2023-11-17T14:13:02Z","creator":"patrickd","access_level":"open_access","file_id":"14550","checksum":"c07860eb82b4d367245f1b589fe5c250","file_size":915079,"file_name":"11-17-23 Updated Koppensteiner et al. raw data.xlsx","success":1,"relation":"main_file","date_created":"2023-11-17T14:13:02Z","content_type":"application/vnd.openxmlformats-officedocument.spreadsheetml.sheet"},{"checksum":"abf84b1699edac4349dc3a92d466fb7b","file_size":544868924,"file_name":"EM_Images.zip","date_updated":"2024-02-06T07:21:43Z","creator":"dernst","access_level":"open_access","file_id":"14942","date_created":"2024-02-06T07:21:43Z","content_type":"application/x-zip-compressed","success":1,"relation":"main_file"}],"fulldoi":"https://doi.org/10.15479/AT:ISTA:13173","article_processing_charge":"No","department":[{"_id":"RySh"}],"year":"2023","date_created":"2023-06-29T13:16:42Z","oa":1,"has_accepted_license":"1","date_published":"2023-07-29T00:00:00Z","tmp":{"name":"Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)","image":"/images/cc_by_nc.png","legal_code_url":"https://creativecommons.org/licenses/by-nc/4.0/legalcode","short":"CC BY-NC (4.0)"},"file_date_updated":"2024-02-06T07:21:43Z","status":"public","keyword":["medial habenula","GABAB receptor","vesicle release","Flash and Freeze","Flash and Freeze-fracture"]},{"article_processing_charge":"No","year":"2023","date_created":"2023-07-09T22:01:12Z","acknowledgement":"This work was supported by The Institute of Science and Technology (IST) Austria, the European Union's Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie Grant Agreement No. 793482 (to K.E.) and by the European Research Council (ERC) Grant Agreement No. 694539 (to R.S.). We thank Nicoleta Condruz (IST Austria, Klosterneuburg, Austria) for technical assistance with sample preparation, the Electron Microscopy Facility of IST Austria (Klosterneuburg, Austria) for technical support with EM works, Natalia Baranova (University of Vienna, Vienna, Austria) and Martin Loose (IST Austria, Klosterneuburg, Austria) for advice on liposome preparation, and Yugo Fukazawa (University of Fukui, Fukui, Japan) for comments.","external_id":{"pmid":["37160366"],"isi":["001020132100005"]},"oa":1,"article_type":"original","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)"},"day":"07","volume":43,"intvolume":"        43","citation":{"mla":"Eguchi, Kohgaku, et al. “Nanoscale Phosphoinositide Distribution on Cell Membranes of Mouse Cerebellar Neurons.” <i>The Journal of Neuroscience</i>, vol. 43, no. 23, Society for Neuroscience, 2023, pp. 4197–216, doi:<a href=\"https://doi.org/10.1523/JNEUROSCI.1514-22.2023\">10.1523/JNEUROSCI.1514-22.2023</a>.","short":"K. Eguchi, E. Le Monnier, R. Shigemoto, The Journal of Neuroscience 43 (2023) 4197–4216.","chicago":"Eguchi, Kohgaku, Elodie Le Monnier, and Ryuichi Shigemoto. “Nanoscale Phosphoinositide Distribution on Cell Membranes of Mouse Cerebellar Neurons.” <i>The Journal of Neuroscience</i>. Society for Neuroscience, 2023. <a href=\"https://doi.org/10.1523/JNEUROSCI.1514-22.2023\">https://doi.org/10.1523/JNEUROSCI.1514-22.2023</a>.","ista":"Eguchi K, Le Monnier E, Shigemoto R. 2023. Nanoscale phosphoinositide distribution on cell membranes of mouse cerebellar neurons. The Journal of Neuroscience. 43(23), 4197–4216.","apa":"Eguchi, K., Le Monnier, E., &#38; Shigemoto, R. (2023). Nanoscale phosphoinositide distribution on cell membranes of mouse cerebellar neurons. <i>The Journal of Neuroscience</i>. Society for Neuroscience. <a href=\"https://doi.org/10.1523/JNEUROSCI.1514-22.2023\">https://doi.org/10.1523/JNEUROSCI.1514-22.2023</a>","ieee":"K. Eguchi, E. Le Monnier, and R. Shigemoto, “Nanoscale phosphoinositide distribution on cell membranes of mouse cerebellar neurons,” <i>The Journal of Neuroscience</i>, vol. 43, no. 23. Society for Neuroscience, pp. 4197–4216, 2023.","ama":"Eguchi K, Le Monnier E, Shigemoto R. Nanoscale phosphoinositide distribution on cell membranes of mouse cerebellar neurons. <i>The Journal of Neuroscience</i>. 2023;43(23):4197-4216. doi:<a href=\"https://doi.org/10.1523/JNEUROSCI.1514-22.2023\">10.1523/JNEUROSCI.1514-22.2023</a>"},"project":[{"grant_number":"793482","_id":"2659CC84-B435-11E9-9278-68D0E5697425","name":"Ultrastructural analysis of phosphoinositides in nerve terminals: distribution, dynamics and physiological roles in synaptic transmission","call_identifier":"H2020"},{"call_identifier":"H2020","name":"In situ analysis of single channel subunit composition in neurons: physiological implication in synaptic plasticity and behaviour","_id":"25CA28EA-B435-11E9-9278-68D0E5697425","grant_number":"694539"}],"title":"Nanoscale phosphoinositide distribution on cell membranes of mouse cerebellar neurons","date_updated":"2025-04-14T07:27:15Z","author":[{"full_name":"Eguchi, Kohgaku","orcid":"0000-0002-6170-2546","first_name":"Kohgaku","last_name":"Eguchi","id":"2B7846DC-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Le Monnier, Elodie","last_name":"Le Monnier","id":"3B59276A-F248-11E8-B48F-1D18A9856A87","first_name":"Elodie"},{"first_name":"Ryuichi","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","last_name":"Shigemoto","full_name":"Shigemoto, Ryuichi","orcid":"0000-0001-8761-9444"}],"abstract":[{"text":"Phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) plays an essential role in neuronal activities through interaction with various proteins involved in signaling at membranes. However, the distribution pattern of PI(4,5)P2 and the association with these proteins on the neuronal cell membranes remain elusive. In this study, we established a method for visualizing PI(4,5)P2 by SDS-digested freeze-fracture replica labeling (SDS-FRL) to investigate the quantitative nanoscale distribution of PI(4,5)P2 in cryo-fixed brain. We demonstrate that PI(4,5)P2 forms tiny clusters with a mean size of ∼1000 nm2 rather than randomly distributed in cerebellar neuronal membranes in male C57BL/6J mice. These clusters show preferential accumulation in specific membrane compartments of different cell types, in particular, in Purkinje cell (PC) spines and granule cell (GC) presynaptic active zones. Furthermore, we revealed extensive association of PI(4,5)P2 with CaV2.1 and GIRK3 across different membrane compartments, whereas its association with mGluR1α was compartment specific. These results suggest that our SDS-FRL method provides valuable insights into the physiological functions of PI(4,5)P2 in neurons.","lang":"eng"}],"acknowledged_ssus":[{"_id":"EM-Fac"}],"quality_controlled":"1","corr_author":"1","file":[{"success":1,"relation":"main_file","date_created":"2023-07-10T09:04:58Z","content_type":"application/pdf","access_level":"open_access","creator":"alisjak","date_updated":"2023-07-10T09:04:58Z","file_id":"13205","file_size":7794425,"checksum":"70b2141870e0bf1c94fd343e18fdbc32","file_name":"2023_JN_Eguchi.pdf"}],"publication_identifier":{"issn":["0270-6474"],"eissn":["1529-2401"]},"doi":"10.1523/JNEUROSCI.1514-22.2023","fulldoi":"https://doi.org/10.1523/JNEUROSCI.1514-22.2023","department":[{"_id":"RySh"}],"ec_funded":1,"date_published":"2023-06-07T00:00:00Z","has_accepted_license":"1","pmid":1,"file_date_updated":"2023-07-10T09:04:58Z","status":"public","issue":"23","ddc":["570"],"month":"06","_id":"13202","oa_version":"Published Version","scopus_import":"1","isi":1,"page":"4197-4216","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publication_status":"published","language":[{"iso":"eng"}],"publication":"The Journal of Neuroscience","type":"journal_article","publisher":"Society for Neuroscience"},{"publisher":"Springer Nature","type":"journal_article","publication":"Nature Communications","language":[{"iso":"eng"}],"user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","publication_status":"published","month":"08","ddc":["570"],"isi":1,"_id":"14253","scopus_import":"1","oa_version":"Published Version","pmid":1,"status":"public","file_date_updated":"2023-09-06T06:50:07Z","has_accepted_license":"1","date_published":"2023-08-26T00:00:00Z","fulldoi":"https://doi.org/10.1038/s41467-023-40930-6","department":[{"_id":"RySh"}],"quality_controlled":"1","file":[{"file_id":"14270","access_level":"open_access","creator":"dernst","date_updated":"2023-09-06T06:50:07Z","file_name":"2023_NatureComm_Vierra.pdf","checksum":"6ab8aab4e957f626a09a1c73db3388fb","file_size":9412549,"relation":"main_file","success":1,"content_type":"application/pdf","date_created":"2023-09-06T06:50:07Z"}],"doi":"10.1038/s41467-023-40930-6","publication_identifier":{"eissn":["2041-1723"]},"author":[{"full_name":"Vierra, Nicholas C.","first_name":"Nicholas C.","last_name":"Vierra"},{"last_name":"Ribeiro-Silva","first_name":"Luisa","full_name":"Ribeiro-Silva, Luisa"},{"first_name":"Michael","last_name":"Kirmiz","full_name":"Kirmiz, Michael"},{"full_name":"Van Der List, Deborah","last_name":"Van Der List","first_name":"Deborah"},{"full_name":"Bhandari, Pradeep","orcid":"0000-0003-0863-4481","first_name":"Pradeep","last_name":"Bhandari","id":"45EDD1BC-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Mack","first_name":"Olivia A.","full_name":"Mack, Olivia A."},{"first_name":"James","last_name":"Carroll","full_name":"Carroll, James"},{"full_name":"Le Monnier, Elodie","first_name":"Elodie","id":"3B59276A-F248-11E8-B48F-1D18A9856A87","last_name":"Le Monnier"},{"full_name":"Aicher, Sue A.","first_name":"Sue A.","last_name":"Aicher"},{"orcid":"0000-0001-8761-9444","full_name":"Shigemoto, Ryuichi","first_name":"Ryuichi","last_name":"Shigemoto","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Trimmer, James S.","first_name":"James S.","last_name":"Trimmer"}],"abstract":[{"text":"Junctions between the endoplasmic reticulum (ER) and the plasma membrane (PM) are specialized membrane contacts ubiquitous in eukaryotic cells. Concentration of intracellular signaling machinery near ER-PM junctions allows these domains to serve critical roles in lipid and Ca2+ signaling and homeostasis. Subcellular compartmentalization of protein kinase A (PKA) signaling also regulates essential cellular functions, however, no specific association between PKA and ER-PM junctional domains is known. Here, we show that in brain neurons type I PKA is directed to Kv2.1 channel-dependent ER-PM junctional domains via SPHKAP, a type I PKA-specific anchoring protein. SPHKAP association with type I PKA regulatory subunit RI and ER-resident VAP proteins results in the concentration of type I PKA between stacked ER cisternae associated with ER-PM junctions. This ER-associated PKA signalosome enables reciprocal regulation between PKA and Ca2+ signaling machinery to support Ca2+ influx and excitation-transcription coupling. These data reveal that neuronal ER-PM junctions support a receptor-independent form of PKA signaling driven by membrane depolarization and intracellular Ca2+, allowing conversion of information encoded in electrical signals into biochemical changes universally recognized throughout the cell.","lang":"eng"}],"title":"Neuronal ER-plasma membrane junctions couple excitation to Ca2+-activated PKA signaling","date_updated":"2025-09-09T12:50:49Z","day":"26","intvolume":"        14","citation":{"chicago":"Vierra, Nicholas C., Luisa Ribeiro-Silva, Michael Kirmiz, Deborah Van Der List, Pradeep Bhandari, Olivia A. Mack, James Carroll, et al. “Neuronal ER-Plasma Membrane Junctions Couple Excitation to Ca2+-Activated PKA Signaling.” <i>Nature Communications</i>. Springer Nature, 2023. <a href=\"https://doi.org/10.1038/s41467-023-40930-6\">https://doi.org/10.1038/s41467-023-40930-6</a>.","short":"N.C. Vierra, L. Ribeiro-Silva, M. Kirmiz, D. Van Der List, P. Bhandari, O.A. Mack, J. Carroll, E. Le Monnier, S.A. Aicher, R. Shigemoto, J.S. Trimmer, Nature Communications 14 (2023).","mla":"Vierra, Nicholas C., et al. “Neuronal ER-Plasma Membrane Junctions Couple Excitation to Ca2+-Activated PKA Signaling.” <i>Nature Communications</i>, vol. 14, 5231, Springer Nature, 2023, doi:<a href=\"https://doi.org/10.1038/s41467-023-40930-6\">10.1038/s41467-023-40930-6</a>.","ieee":"N. C. Vierra <i>et al.</i>, “Neuronal ER-plasma membrane junctions couple excitation to Ca2+-activated PKA signaling,” <i>Nature Communications</i>, vol. 14. Springer Nature, 2023.","apa":"Vierra, N. C., Ribeiro-Silva, L., Kirmiz, M., Van Der List, D., Bhandari, P., Mack, O. A., … Trimmer, J. S. (2023). Neuronal ER-plasma membrane junctions couple excitation to Ca2+-activated PKA signaling. <i>Nature Communications</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41467-023-40930-6\">https://doi.org/10.1038/s41467-023-40930-6</a>","ista":"Vierra NC, Ribeiro-Silva L, Kirmiz M, Van Der List D, Bhandari P, Mack OA, Carroll J, Le Monnier E, Aicher SA, Shigemoto R, Trimmer JS. 2023. Neuronal ER-plasma membrane junctions couple excitation to Ca2+-activated PKA signaling. Nature Communications. 14, 5231.","ama":"Vierra NC, Ribeiro-Silva L, Kirmiz M, et al. Neuronal ER-plasma membrane junctions couple excitation to Ca2+-activated PKA signaling. <i>Nature Communications</i>. 2023;14. doi:<a href=\"https://doi.org/10.1038/s41467-023-40930-6\">10.1038/s41467-023-40930-6</a>"},"volume":14,"article_number":"5231","article_type":"original","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)"},"acknowledgement":"We thank Kayla Templeton and Peter Turcanu for technical assistance, Michelle Salemi for assistance with LC-MS data acquisition and analysis, Dr. Belvin Gong for advice on monoclonal antibody generation, Drs. Maria Casas Prat and Eamonn Dickson for assistance with super-resolution TIRF microscopy, Dr. Oscar Cerda for assistance with the design of TAT-FFAT peptides, Dr. Fernando Santana for helpful discussions, and Dr. Jodi Nunnari for a careful reading of our manuscript. We also thank Dr. Alan Howe, Dr. Sohum Mehta, and Dr. Jin Zhang for providing plasmids used in this study. This project was funded by NIH Grants R01NS114210 and R21NS101648 (J.S.T.), and F32NS108519 (N.C.V.).","oa":1,"external_id":{"isi":["001064563400013"],"pmid":["37633939"]},"article_processing_charge":"Yes","year":"2023","date_created":"2023-09-03T22:01:14Z"},{"date_updated":"2026-10-01T12:17:26Z","related_material":{"record":[{"id":"18445","relation":"used_in_publication","status":"public"}]},"main_file_link":[{"url":"https://doi.org/10.6084/m9.figshare.22680433","open_access":"1"}],"title":"Glutamate and GABA neurons share cascading Onecut3/NAV2-driven differentiation trajectories in the developing hypothalamus","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","publisher":"Repository","type":"research_data_reference","author":[{"full_name":"Zupancic, Maja","first_name":"Maja","last_name":"Zupancic"},{"last_name":"Keimpema","first_name":"Erik","full_name":"Keimpema, Erik"},{"full_name":"Tretiakov, Evgenii","last_name":"Tretiakov","first_name":"Evgenii"},{"first_name":"Pradeep","last_name":"Bhandari","full_name":"Bhandari, Pradeep"},{"last_name":"Eder","first_name":"Stephanie","full_name":"Eder, Stephanie"},{"last_name":"Lev","first_name":"Itamar","full_name":"Lev, Itamar"},{"full_name":"Härtig, Wolfgang","first_name":"Wolfgang","last_name":"Härtig"},{"first_name":"Manuel","last_name":"Zimmer","full_name":"Zimmer, Manuel"},{"first_name":"Frederic","last_name":"Clotman","full_name":"Clotman, Frederic"},{"full_name":"Harkany, Tibor","last_name":"Harkany","first_name":"Tibor"}],"abstract":[{"text":"## Rationale:\r\nDifferentiation trajectories to generate specialized cellular features rely on sets of transcription factors (TFs) whose temporal dynamics and coexistence underlie morphological and neurochemical divergence among neurons and neuroendocrine cells. Even though transcriptional programs were extensively studied in the developing nervous system, the coupling of TFs to effector gene networks that time and shape the morphogenesis of these polarized cells is less known.\r\n\r\n## Results:\r\nHere, we make the curious observation that evolutionarily conserved Onecut3, a subordinate in the Onecut TF family known to control fate selection in progenitors, is instead expressed in fate-restricted neuroblasts in the vertebrate hypothalamus. In particular, a pool of Ascl1-containing progenitors in the midgestational mouse hypothalamus gives rise to both GABA and glutamate neurons destined to the periventricular and lateral hypothalamus, respectively, which uniformly upregulate Onecut3 only when exiting the proliferative zone of the 3rd ventricle. By combining single-cell RNA-seq, genetic Onecut3 reporters, gain-of-function models in vitro, and loss-of-function analysis in early-developing mice and C. elegans, we identify that Onecut3 instructs neuronal differentiation and maturation, through a Navigator-2 pathway to modulate neuritogenesis and leading process motility.\r\n\r\n\r\n## Conclusion:\r\nOnecut3 executes an unexpected function by inducing cytoskeletal modifications of key importance for neuronal maturation and network integration during the morphogenesis of many neuronal phenotypes in the vertebrate hypothalamus.","lang":"eng"}],"_id":"22961","oa_version":"None","ddc":["570"],"month":"04","citation":{"ama":"Zupancic M, Keimpema E, Tretiakov E, et al. Glutamate and GABA neurons share cascading Onecut3/NAV2-driven differentiation trajectories in the developing hypothalamus. 2023. doi:<a href=\"https://doi.org/10.6084/m9.figshare.22680433\">10.6084/m9.figshare.22680433</a>","short":"M. Zupancic, E. Keimpema, E. Tretiakov, P. Bhandari, S. Eder, I. Lev, W. Härtig, M. Zimmer, F. Clotman, T. Harkany, (2023).","mla":"Zupancic, Maja, et al. <i>Glutamate and GABA Neurons Share Cascading Onecut3/NAV2-Driven Differentiation Trajectories in the Developing Hypothalamus</i>. Repository, 2023, doi:<a href=\"https://doi.org/10.6084/m9.figshare.22680433\">10.6084/m9.figshare.22680433</a>.","chicago":"Zupancic, Maja, Erik Keimpema, Evgenii Tretiakov, Pradeep Bhandari, Stephanie Eder, Itamar Lev, Wolfgang Härtig, Manuel Zimmer, Frederic Clotman, and Tibor Harkany. “Glutamate and GABA Neurons Share Cascading Onecut3/NAV2-Driven Differentiation Trajectories in the Developing Hypothalamus.” Repository, 2023. <a href=\"https://doi.org/10.6084/m9.figshare.22680433\">https://doi.org/10.6084/m9.figshare.22680433</a>.","ista":"Zupancic M, Keimpema E, Tretiakov E, Bhandari P, Eder S, Lev I, Härtig W, Zimmer M, Clotman F, Harkany T. 2023. Glutamate and GABA neurons share cascading Onecut3/NAV2-driven differentiation trajectories in the developing hypothalamus, Repository, <a href=\"https://doi.org/10.6084/m9.figshare.22680433\">10.6084/m9.figshare.22680433</a>.","ieee":"M. Zupancic <i>et al.</i>, “Glutamate and GABA neurons share cascading Onecut3/NAV2-driven differentiation trajectories in the developing hypothalamus.” Repository, 2023.","apa":"Zupancic, M., Keimpema, E., Tretiakov, E., Bhandari, P., Eder, S., Lev, I., … Harkany, T. (2023). Glutamate and GABA neurons share cascading Onecut3/NAV2-driven differentiation trajectories in the developing hypothalamus. Repository. <a href=\"https://doi.org/10.6084/m9.figshare.22680433\">https://doi.org/10.6084/m9.figshare.22680433</a>"},"day":"23","oa":1,"date_published":"2023-04-23T00:00:00Z","status":"public","doi":"10.6084/m9.figshare.22680433","OA_place":"repository","department":[{"_id":"RySh"}],"date_created":"2026-09-17T11:23:46Z","year":"2023","article_processing_charge":"No","fulldoi":"https://doi.org/10.6084/m9.figshare.22680433","OA_type":"green"},{"has_accepted_license":"1","date_published":"2023-04-06T00:00:00Z","degree_awarded":"PhD","file_date_updated":"2024-04-08T22:30:03Z","status":"public","corr_author":"1","acknowledged_ssus":[{"_id":"EM-Fac"},{"_id":"Bio"},{"_id":"PreCl"}],"file":[{"relation":"main_file","content_type":"application/pdf","date_created":"2023-04-07T06:16:06Z","file_id":"12814","date_updated":"2024-04-08T22:30:03Z","creator":"cchlebak","access_level":"open_access","embargo":"2024-04-07","file_name":"Thesis_CatarinaAlcarva_final pdfA.pdf","checksum":"35b5997d2b0acb461f9d33d073da0df5","file_size":9881969},{"relation":"source_file","date_created":"2023-04-07T06:17:11Z","content_type":"application/pdf","embargo_to":"open_access","access_level":"closed","creator":"cchlebak","date_updated":"2024-04-08T22:30:03Z","file_id":"12815","checksum":"81198f63c294890f6d58e8b29782efdc","file_size":44201583,"file_name":"Thesis_CatarinaAlcarva_final_for printing.pdf"},{"date_created":"2023-04-07T06:18:05Z","embargo_to":"open_access","content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document","relation":"source_file","file_size":84731244,"checksum":"0317bf7f457bb585f99d453ffa69eb53","file_name":"Thesis_CatarinaAlcarva_final.docx","date_updated":"2024-04-08T22:30:03Z","creator":"cchlebak","access_level":"closed","file_id":"12816"}],"doi":"10.15479/at:ista:12809","publication_identifier":{"issn":["2663-337X"]},"fulldoi":"https://doi.org/10.15479/at:ista:12809","OA_place":"publisher","department":[{"_id":"GradSch"},{"_id":"RySh"}],"language":[{"iso":"eng"}],"publication_status":"published","user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","supervisor":[{"last_name":"Shigemoto","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","first_name":"Ryuichi","orcid":"0000-0001-8761-9444","full_name":"Shigemoto, Ryuichi"}],"publisher":"Institute of Science and Technology Austria","type":"dissertation","month":"04","ddc":["570"],"oa_version":"Published Version","_id":"12809","page":"115","oa":1,"article_processing_charge":"No","year":"2023","date_created":"2023-04-06T07:54:09Z","title":"Plasticity in the cerebellum: What molecular mechanisms are behind physiological learning","date_updated":"2026-04-07T13:53:28Z","abstract":[{"lang":"eng","text":"Understanding the mechanisms of learning and memory formation has always been one of\r\nthe main goals in neuroscience. Already Pavlov (1927) in his early days has used his classic\r\nconditioning experiments to study the neural mechanisms governing behavioral adaptation.\r\nWhat was not known back then was that the part of the brain that is largely responsible for\r\nthis type of associative learning is the cerebellum.\r\nSince then, plenty of theories on cerebellar learning have emerged. Despite their differences,\r\none thing they all have in common is that learning relies on synaptic and intrinsic plasticity.\r\nThe goal of my PhD project was to unravel the molecular mechanisms underlying synaptic\r\nplasticity in two synapses that have been shown to be implicated in motor learning, in an\r\neffort to understand how learning and memory formation are processed in the cerebellum.\r\nOne of the earliest and most well-known cerebellar theories postulates that motor learning\r\nlargely depends on long-term depression at the parallel fiber-Purkinje cell (PC-PC) synapse.\r\nHowever, the discovery of other types of plasticity in the cerebellar circuitry, like long-term\r\npotentiation (LTP) at the PC-PC synapse, potentiation of molecular layer interneurons (MLIs),\r\nand plasticity transfer from the cortex to the cerebellar/ vestibular nuclei has increased the\r\npopularity of the idea that multiple sites of plasticity might be involved in learning.\r\nStill a lot remains unknown about the molecular mechanisms responsible for these types of\r\nplasticity and whether they occur during physiological learning.\r\nIn the first part of this thesis we have analyzed the variation and nanodistribution of voltagegated calcium channels (VGCCs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid\r\ntype glutamate receptors (AMPARs) on the parallel fiber-Purkinje cell synapse after vestibuloocular reflex phase reversal adaptation, a behavior that has been suggested to rely on PF-PC\r\nLTP. We have found that on the last day of adaptation there is no learning trace in form of\r\nVGCCs nor AMPARs variation at the PF-PC synapse, but instead a decrease in the number of\r\nPF-PC synapses. These data seem to support the view that learning is only stored in the\r\ncerebellar cortex in an initial learning phase, being transferred later to the vestibular nuclei.\r\nNext, we have studied the role of MLIs in motor learning using a relatively simple and well characterized behavioral paradigm – horizontal optokinetic reflex (HOKR) adaptation. We\r\nhave found behavior-induced MLI potentiation in form of release probability increase that\r\ncould be explained by the increase of VGCCs at the presynaptic side. Our results strengthen\r\nthe idea of distributed cerebellar plasticity contributing to learning and provide a novel\r\nmechanism for release probability increase. "}],"author":[{"last_name":"Alcarva","id":"3A96634C-F248-11E8-B48F-1D18A9856A87","first_name":"Catarina","full_name":"Alcarva, Catarina"}],"day":"06","alternative_title":["ISTA Thesis"],"project":[{"name":"Plasticity in the cerebellum: Which molecular mechanisms are behind physiological learning?","_id":"267DFB90-B435-11E9-9278-68D0E5697425"}],"citation":{"ama":"Alcarva C. Plasticity in the cerebellum: What molecular mechanisms are behind physiological learning. 2023. doi:<a href=\"https://doi.org/10.15479/at:ista:12809\">10.15479/at:ista:12809</a>","apa":"Alcarva, C. (2023). <i>Plasticity in the cerebellum: What molecular mechanisms are behind physiological learning</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/at:ista:12809\">https://doi.org/10.15479/at:ista:12809</a>","ieee":"C. Alcarva, “Plasticity in the cerebellum: What molecular mechanisms are behind physiological learning,” Institute of Science and Technology Austria, 2023.","ista":"Alcarva C. 2023. Plasticity in the cerebellum: What molecular mechanisms are behind physiological learning. Institute of Science and Technology Austria.","chicago":"Alcarva, Catarina. “Plasticity in the Cerebellum: What Molecular Mechanisms Are behind Physiological Learning.” Institute of Science and Technology Austria, 2023. <a href=\"https://doi.org/10.15479/at:ista:12809\">https://doi.org/10.15479/at:ista:12809</a>.","short":"C. Alcarva, Plasticity in the Cerebellum: What Molecular Mechanisms Are behind Physiological Learning, Institute of Science and Technology Austria, 2023.","mla":"Alcarva, Catarina. <i>Plasticity in the Cerebellum: What Molecular Mechanisms Are behind Physiological Learning</i>. Institute of Science and Technology Austria, 2023, doi:<a href=\"https://doi.org/10.15479/at:ista:12809\">10.15479/at:ista:12809</a>."}},{"pmid":1,"status":"public","issue":"Supplement_1","date_published":"2022-03-01T00:00:00Z","fulldoi":"https://doi.org/10.1093/jmicro/dfab048","ec_funded":1,"department":[{"_id":"RySh"}],"quality_controlled":"1","corr_author":"1","doi":"10.1093/jmicro/dfab048","publication_identifier":{"eissn":["2050-5701"],"issn":["2050-5698"]},"type":"journal_article","publisher":"Oxford University Press","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publication_status":"published","publication":"Microscopy","language":[{"iso":"eng"}],"main_file_link":[{"url":"https://doi.org/10.1093/jmicro/dfab048","open_access":"1"}],"page":"i72-i80","month":"03","ddc":["570"],"scopus_import":"1","_id":"10889","oa_version":"Published Version","isi":1,"article_type":"original","acknowledgement":"European Research Council Advanced Grant (694539 to R.S.).","external_id":{"pmid":["35275179"],"isi":["000768384100011"]},"oa":1,"article_processing_charge":"No","year":"2022","date_created":"2022-03-20T23:01:39Z","author":[{"first_name":"Ryuichi","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","last_name":"Shigemoto","orcid":"0000-0001-8761-9444","full_name":"Shigemoto, Ryuichi"}],"abstract":[{"text":"Genetically encoded tags have introduced extensive lines of application from purification of tagged proteins to their visualization at the single molecular, cellular, histological and whole-body levels. Combined with other rapidly developing technologies such as clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system, proteomics, super-resolution microscopy and proximity labeling, a large variety of genetically encoded tags have been developed in the last two decades. In this review, I focus on the current status of tag development for electron microscopic (EM) visualization of proteins with metal particle labeling. Compared with conventional immunoelectron microscopy using gold particles, tag-mediated metal particle labeling has several advantages that could potentially improve the sensitivity, spatial and temporal resolution, and applicability to a wide range of proteins of interest (POIs). It may enable researchers to detect single molecules in situ, allowing the quantitative measurement of absolute numbers and exact localization patterns of POI in the ultrastructural context. Thus, genetically encoded tags for EM could revolutionize the field as green fluorescence protein did for light microscopy, although we still have many challenges to overcome before reaching this goal.","lang":"eng"}],"title":"Electron microscopic visualization of single molecules by tag-mediated metal particle labeling","date_updated":"2026-06-18T10:44:57Z","day":"01","volume":71,"project":[{"call_identifier":"H2020","grant_number":"694539","name":"In situ analysis of single channel subunit composition in neurons: physiological implication in synaptic plasticity and behaviour","_id":"25CA28EA-B435-11E9-9278-68D0E5697425"}],"intvolume":"        71","citation":{"ama":"Shigemoto R. Electron microscopic visualization of single molecules by tag-mediated metal particle labeling. <i>Microscopy</i>. 2022;71(Supplement_1):i72-i80. doi:<a href=\"https://doi.org/10.1093/jmicro/dfab048\">10.1093/jmicro/dfab048</a>","ista":"Shigemoto R. 2022. Electron microscopic visualization of single molecules by tag-mediated metal particle labeling. Microscopy. 71(Supplement_1), i72–i80.","ieee":"R. Shigemoto, “Electron microscopic visualization of single molecules by tag-mediated metal particle labeling,” <i>Microscopy</i>, vol. 71, no. Supplement_1. Oxford University Press, pp. i72–i80, 2022.","apa":"Shigemoto, R. (2022). Electron microscopic visualization of single molecules by tag-mediated metal particle labeling. <i>Microscopy</i>. Oxford University Press. <a href=\"https://doi.org/10.1093/jmicro/dfab048\">https://doi.org/10.1093/jmicro/dfab048</a>","short":"R. Shigemoto, Microscopy 71 (2022) i72–i80.","mla":"Shigemoto, Ryuichi. “Electron Microscopic Visualization of Single Molecules by Tag-Mediated Metal Particle Labeling.” <i>Microscopy</i>, vol. 71, no. Supplement_1, Oxford University Press, 2022, pp. i72–80, doi:<a href=\"https://doi.org/10.1093/jmicro/dfab048\">10.1093/jmicro/dfab048</a>.","chicago":"Shigemoto, Ryuichi. “Electron Microscopic Visualization of Single Molecules by Tag-Mediated Metal Particle Labeling.” <i>Microscopy</i>. Oxford University Press, 2022. <a href=\"https://doi.org/10.1093/jmicro/dfab048\">https://doi.org/10.1093/jmicro/dfab048</a>."}},{"type":"journal_article","publisher":"Frontiers","publication_status":"published","user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","language":[{"iso":"eng"}],"publication":"Frontiers in Neuroanatomy","ddc":["570"],"month":"02","_id":"10890","scopus_import":"1","oa_version":"Published Version","isi":1,"pmid":1,"status":"public","file_date_updated":"2022-03-21T09:41:19Z","date_published":"2022-02-24T00:00:00Z","has_accepted_license":"1","fulldoi":"https://doi.org/10.3389/fnana.2022.846615","ec_funded":1,"department":[{"_id":"RySh"}],"quality_controlled":"1","corr_author":"1","publication_identifier":{"eissn":["1662-5129"]},"file":[{"access_level":"open_access","date_updated":"2022-03-21T09:41:19Z","creator":"dernst","file_id":"10911","checksum":"51ec9b90e7da919e22c01a15489eaacd","file_size":2416395,"file_name":"2022_FrontiersNeuroanatomy_Eguchi.pdf","success":1,"relation":"main_file","date_created":"2022-03-21T09:41:19Z","content_type":"application/pdf"}],"doi":"10.3389/fnana.2022.846615","author":[{"full_name":"Eguchi, Kohgaku","orcid":"0000-0002-6170-2546","last_name":"Eguchi","id":"2B7846DC-F248-11E8-B48F-1D18A9856A87","first_name":"Kohgaku"},{"first_name":"Jacqueline-Claire","last_name":"Montanaro-Punzengruber","id":"3786AB44-F248-11E8-B48F-1D18A9856A87","full_name":"Montanaro-Punzengruber, Jacqueline-Claire"},{"first_name":"Elodie","last_name":"Le Monnier","id":"3B59276A-F248-11E8-B48F-1D18A9856A87","full_name":"Le Monnier, Elodie"},{"first_name":"Ryuichi","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","last_name":"Shigemoto","orcid":"0000-0001-8761-9444","full_name":"Shigemoto, Ryuichi"}],"abstract":[{"lang":"eng","text":"Upon the arrival of action potentials at nerve terminals, neurotransmitters are released from synaptic vesicles (SVs) by exocytosis. CaV2.1, 2.2, and 2.3 are the major subunits of the voltage-gated calcium channel (VGCC) responsible for increasing intraterminal calcium levels and triggering SV exocytosis in the central nervous system (CNS) synapses. The two-dimensional analysis of CaV2 distributions using sodium dodecyl sulfate (SDS)-digested freeze-fracture replica labeling (SDS-FRL) has revealed their numbers, densities, and nanoscale clustering patterns in individual presynaptic active zones. The variation in these properties affects the coupling of VGCCs with calcium sensors on SVs, synaptic efficacy, and temporal precision of transmission. In this study, we summarize how the morphological parameters of CaV2 distribution obtained using SDS-FRL differ depending on the different types of synapses and could correspond to functional properties in synaptic transmission."}],"title":"The number and distinct clustering patterns of voltage-gated Calcium channels in nerve terminals","date_updated":"2026-04-16T08:18:54Z","day":"24","volume":16,"project":[{"call_identifier":"H2020","name":"In situ analysis of single channel subunit composition in neurons: physiological implication in synaptic plasticity and behaviour","_id":"25CA28EA-B435-11E9-9278-68D0E5697425","grant_number":"694539"},{"_id":"05970B30-7A3F-11EA-A408-12923DDC885E","name":"LGI1 antibody-induced pathophysiology in synapses","grant_number":"I04638"}],"citation":{"ama":"Eguchi K, Montanaro-Punzengruber J-C, Le Monnier E, Shigemoto R. The number and distinct clustering patterns of voltage-gated Calcium channels in nerve terminals. <i>Frontiers in Neuroanatomy</i>. 2022;16. doi:<a href=\"https://doi.org/10.3389/fnana.2022.846615\">10.3389/fnana.2022.846615</a>","apa":"Eguchi, K., Montanaro-Punzengruber, J.-C., Le Monnier, E., &#38; Shigemoto, R. (2022). The number and distinct clustering patterns of voltage-gated Calcium channels in nerve terminals. <i>Frontiers in Neuroanatomy</i>. Frontiers. <a href=\"https://doi.org/10.3389/fnana.2022.846615\">https://doi.org/10.3389/fnana.2022.846615</a>","ieee":"K. Eguchi, J.-C. Montanaro-Punzengruber, E. Le Monnier, and R. Shigemoto, “The number and distinct clustering patterns of voltage-gated Calcium channels in nerve terminals,” <i>Frontiers in Neuroanatomy</i>, vol. 16. Frontiers, 2022.","ista":"Eguchi K, Montanaro-Punzengruber J-C, Le Monnier E, Shigemoto R. 2022. The number and distinct clustering patterns of voltage-gated Calcium channels in nerve terminals. Frontiers in Neuroanatomy. 16, 846615.","chicago":"Eguchi, Kohgaku, Jacqueline-Claire Montanaro-Punzengruber, Elodie Le Monnier, and Ryuichi Shigemoto. “The Number and Distinct Clustering Patterns of Voltage-Gated Calcium Channels in Nerve Terminals.” <i>Frontiers in Neuroanatomy</i>. Frontiers, 2022. <a href=\"https://doi.org/10.3389/fnana.2022.846615\">https://doi.org/10.3389/fnana.2022.846615</a>.","mla":"Eguchi, Kohgaku, et al. “The Number and Distinct Clustering Patterns of Voltage-Gated Calcium Channels in Nerve Terminals.” <i>Frontiers in Neuroanatomy</i>, vol. 16, 846615, Frontiers, 2022, doi:<a href=\"https://doi.org/10.3389/fnana.2022.846615\">10.3389/fnana.2022.846615</a>.","short":"K. Eguchi, J.-C. Montanaro-Punzengruber, E. Le Monnier, R. Shigemoto, Frontiers in Neuroanatomy 16 (2022)."},"intvolume":"        16","article_number":"846615","article_type":"original","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)"},"acknowledgement":"This work was supported by the European Research Council advanced grant No. 694539 and the joint German-Austrian DFG and FWF project SYNABS (FWF: I-4638-B) to RS.\r\nThe authors thank Walter Kaufmann for his critical comments on the manuscript.","external_id":{"isi":["000766662700001"],"pmid":["35280978"]},"oa":1,"article_processing_charge":"No","date_created":"2022-03-20T23:01:39Z","year":"2022"},{"type":"journal_article","publisher":"Wiley","main_file_link":[{"url":"https://doi.org/10.1002/chem.202200807","open_access":"1"}],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publication_status":"published","publication":"Chemistry - A European Journal","language":[{"iso":"eng"}],"_id":"11333","oa_version":"Published Version","scopus_import":"1","isi":1,"ddc":["570"],"month":"05","issue":"30","status":"public","pmid":1,"date_published":"2022-05-25T00:00:00Z","department":[{"_id":"RySh"}],"fulldoi":"https://doi.org/10.1002/chem.202200807","publication_identifier":{"eissn":["1521-3765"],"issn":["0947-6539"]},"doi":"10.1002/chem.202200807","quality_controlled":"1","abstract":[{"text":"Adenosine triphosphate (ATP) is the energy source for various biochemical processes and biomolecular motors in living things. Development of ATP antagonists and their stimuli-controlled actions offer a novel approach to regulate biological processes. Herein, we developed azobenzene-based photoswitchable ATP antagonists for controlling the activity of motor proteins; cytoplasmic and axonemal dyneins. The new ATP antagonists showed reversible photoswitching of cytoplasmic dynein activity in an in vitro dynein-microtubule system due to the trans and cis photoisomerization of their azobenzene segment. Importantly, our ATP antagonists reversibly regulated the axonemal dynein motor activity for the force generation in a demembranated model of Chlamydomonas reinhardtii. We found that the trans and cis isomers of ATP antagonists significantly differ in their affinity to the ATP binding site.","lang":"eng"}],"author":[{"last_name":"Thayyil","first_name":"Sampreeth","full_name":"Thayyil, Sampreeth"},{"first_name":"Yukinori","last_name":"Nishigami","full_name":"Nishigami, Yukinori"},{"full_name":"Islam, Muhammad J","first_name":"Muhammad J","last_name":"Islam","id":"C94881D2-008F-11EA-8E08-2637E6697425"},{"full_name":"Hashim, P. K.","first_name":"P. K.","last_name":"Hashim"},{"full_name":"Furuta, Ken'Ya","first_name":"Ken'Ya","last_name":"Furuta"},{"full_name":"Oiwa, Kazuhiro","last_name":"Oiwa","first_name":"Kazuhiro"},{"last_name":"Yu","first_name":"Jian","full_name":"Yu, Jian"},{"full_name":"Yao, Min","last_name":"Yao","first_name":"Min"},{"full_name":"Nakagaki, Toshiyuki","last_name":"Nakagaki","first_name":"Toshiyuki"},{"full_name":"Tamaoki, Nobuyuki","last_name":"Tamaoki","first_name":"Nobuyuki"}],"date_updated":"2026-06-18T10:49:46Z","title":"Dynamic control of microbial movement by photoswitchable ATP antagonists","volume":28,"citation":{"ama":"Thayyil S, Nishigami Y, Islam MJ, et al. Dynamic control of microbial movement by photoswitchable ATP antagonists. <i>Chemistry - A European Journal</i>. 2022;28(30). doi:<a href=\"https://doi.org/10.1002/chem.202200807\">10.1002/chem.202200807</a>","ieee":"S. Thayyil <i>et al.</i>, “Dynamic control of microbial movement by photoswitchable ATP antagonists,” <i>Chemistry - A European Journal</i>, vol. 28, no. 30. Wiley, 2022.","apa":"Thayyil, S., Nishigami, Y., Islam, M. J., Hashim, P. K., Furuta, K., Oiwa, K., … Tamaoki, N. (2022). Dynamic control of microbial movement by photoswitchable ATP antagonists. <i>Chemistry - A European Journal</i>. Wiley. <a href=\"https://doi.org/10.1002/chem.202200807\">https://doi.org/10.1002/chem.202200807</a>","ista":"Thayyil S, Nishigami Y, Islam MJ, Hashim PK, Furuta K, Oiwa K, Yu J, Yao M, Nakagaki T, Tamaoki N. 2022. Dynamic control of microbial movement by photoswitchable ATP antagonists. Chemistry - A European Journal. 28(30), e202200807.","chicago":"Thayyil, Sampreeth, Yukinori Nishigami, Muhammad J Islam, P. K. Hashim, Ken’Ya Furuta, Kazuhiro Oiwa, Jian Yu, Min Yao, Toshiyuki Nakagaki, and Nobuyuki Tamaoki. “Dynamic Control of Microbial Movement by Photoswitchable ATP Antagonists.” <i>Chemistry - A European Journal</i>. Wiley, 2022. <a href=\"https://doi.org/10.1002/chem.202200807\">https://doi.org/10.1002/chem.202200807</a>.","mla":"Thayyil, Sampreeth, et al. “Dynamic Control of Microbial Movement by Photoswitchable ATP Antagonists.” <i>Chemistry - A European Journal</i>, vol. 28, no. 30, e202200807, Wiley, 2022, doi:<a href=\"https://doi.org/10.1002/chem.202200807\">10.1002/chem.202200807</a>.","short":"S. Thayyil, Y. Nishigami, M.J. Islam, P.K. Hashim, K. Furuta, K. Oiwa, J. Yu, M. Yao, T. Nakagaki, N. Tamaoki, Chemistry - A European Journal 28 (2022)."},"intvolume":"        28","day":"25","article_number":"e202200807","article_type":"original","external_id":{"pmid":["35332959"],"isi":["000781658800001"]},"oa":1,"year":"2022","date_created":"2022-04-24T22:01:44Z","article_processing_charge":"No"},{"publication_identifier":{"eissn":["2050-084X"]},"doi":"10.7554/eLife.73542","file":[{"file_id":"11421","access_level":"open_access","creator":"cchlebak","date_updated":"2022-05-30T08:09:16Z","file_name":"elife-73542-v2.pdf","file_size":2466296,"checksum":"ccddbd167e00ff8375f12998af497152","relation":"main_file","success":1,"content_type":"application/pdf","date_created":"2022-05-30T08:09:16Z"}],"quality_controlled":"1","department":[{"_id":"RySh"}],"fulldoi":"https://doi.org/10.7554/eLife.73542","has_accepted_license":"1","date_published":"2022-05-05T00:00:00Z","file_date_updated":"2022-05-30T08:09:16Z","status":"public","pmid":1,"isi":1,"scopus_import":"1","_id":"11419","oa_version":"Published Version","ddc":["616"],"month":"05","language":[{"iso":"eng"}],"publication":"eLife","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","publication_status":"published","publisher":"eLife Sciences Publications","type":"journal_article","year":"2022","date_created":"2022-05-29T22:01:54Z","article_processing_charge":"No","oa":1,"external_id":{"isi":["000876231600001"],"pmid":["35471147 "]},"acknowledgement":"We thank Yasuo Ihara, Nobuyuki Nukina, and Takeshi Sakaba for comments and Patrick Stoney for editing this paper. We also thank Shota Okuda and Mikako Matsubara for their contributions in the early stage of this study, and Satoko Wada-Kakuda for technical assistant with in vitro analysis of tau. This research was supported by funding from Okinawa Institute of Science and Technology and from Technology (OIST) and Core Research for the Evolutional Science and Technology of Japan Science and Technology Agency (CREST) to TT, and by Scientific Research on Innovative Areas to TM (Brain Protein Aging and Dementia Control 26117004).","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)"},"article_type":"original","article_number":"e73542","intvolume":"        11","citation":{"ista":"Hori T, Eguchi K, Wang HY, Miyasaka T, Guillaud L, Taoufiq Z, Mahapatra S, Yamada H, Takei K, Takahashi T. 2022. Microtubule assembly by tau impairs endocytosis and neurotransmission via dynamin sequestration in Alzheimer’s disease synapse model. eLife. 11, e73542.","apa":"Hori, T., Eguchi, K., Wang, H. Y., Miyasaka, T., Guillaud, L., Taoufiq, Z., … Takahashi, T. (2022). Microtubule assembly by tau impairs endocytosis and neurotransmission via dynamin sequestration in Alzheimer’s disease synapse model. <i>ELife</i>. eLife Sciences Publications. <a href=\"https://doi.org/10.7554/eLife.73542\">https://doi.org/10.7554/eLife.73542</a>","ieee":"T. Hori <i>et al.</i>, “Microtubule assembly by tau impairs endocytosis and neurotransmission via dynamin sequestration in Alzheimer’s disease synapse model,” <i>eLife</i>, vol. 11. eLife Sciences Publications, 2022.","mla":"Hori, Tetsuya, et al. “Microtubule Assembly by Tau Impairs Endocytosis and Neurotransmission via Dynamin Sequestration in Alzheimer’s Disease Synapse Model.” <i>ELife</i>, vol. 11, e73542, eLife Sciences Publications, 2022, doi:<a href=\"https://doi.org/10.7554/eLife.73542\">10.7554/eLife.73542</a>.","short":"T. Hori, K. Eguchi, H.Y. Wang, T. Miyasaka, L. Guillaud, Z. Taoufiq, S. Mahapatra, H. Yamada, K. Takei, T. Takahashi, ELife 11 (2022).","chicago":"Hori, Tetsuya, Kohgaku Eguchi, Han Ying Wang, Tomohiro Miyasaka, Laurent Guillaud, Zacharie Taoufiq, Satyajit Mahapatra, Hiroshi Yamada, Kohji Takei, and Tomoyuki Takahashi. “Microtubule Assembly by Tau Impairs Endocytosis and Neurotransmission via Dynamin Sequestration in Alzheimer’s Disease Synapse Model.” <i>ELife</i>. eLife Sciences Publications, 2022. <a href=\"https://doi.org/10.7554/eLife.73542\">https://doi.org/10.7554/eLife.73542</a>.","ama":"Hori T, Eguchi K, Wang HY, et al. Microtubule assembly by tau impairs endocytosis and neurotransmission via dynamin sequestration in Alzheimer’s disease synapse model. <i>eLife</i>. 2022;11. doi:<a href=\"https://doi.org/10.7554/eLife.73542\">10.7554/eLife.73542</a>"},"volume":11,"day":"05","date_updated":"2023-08-03T07:15:49Z","title":"Microtubule assembly by tau impairs endocytosis and neurotransmission via dynamin sequestration in Alzheimer's disease synapse model","author":[{"last_name":"Hori","first_name":"Tetsuya","full_name":"Hori, Tetsuya"},{"orcid":"0000-0002-6170-2546","full_name":"Eguchi, Kohgaku","first_name":"Kohgaku","last_name":"Eguchi","id":"2B7846DC-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Wang, Han Ying","first_name":"Han Ying","last_name":"Wang"},{"full_name":"Miyasaka, Tomohiro","last_name":"Miyasaka","first_name":"Tomohiro"},{"first_name":"Laurent","last_name":"Guillaud","full_name":"Guillaud, Laurent"},{"full_name":"Taoufiq, Zacharie","last_name":"Taoufiq","first_name":"Zacharie"},{"first_name":"Satyajit","last_name":"Mahapatra","full_name":"Mahapatra, Satyajit"},{"last_name":"Yamada","first_name":"Hiroshi","full_name":"Yamada, Hiroshi"},{"full_name":"Takei, Kohji","last_name":"Takei","first_name":"Kohji"},{"last_name":"Takahashi","first_name":"Tomoyuki","full_name":"Takahashi, Tomoyuki"}],"abstract":[{"lang":"eng","text":"Elevation of soluble wild-type (WT) tau occurs in synaptic compartments in Alzheimer’s disease. We addressed whether tau elevation affects synaptic transmission at the calyx of Held in slices from mice brainstem. Whole-cell loading of WT human tau (h-tau) in presynaptic terminals at 10–20 µM caused microtubule (MT) assembly and activity-dependent rundown of excitatory neurotransmission. Capacitance measurements revealed that the primary target of WT h-tau is vesicle endocytosis. Blocking MT assembly using nocodazole prevented tau-induced impairments of endocytosis and neurotransmission. Immunofluorescence imaging analyses revealed that MT assembly by WT h-tau loading was associated with an increased MT-bound fraction of the endocytic protein dynamin. A synthetic dodecapeptide corresponding to dynamin 1-pleckstrin-homology domain inhibited MT-dynamin interaction and rescued tau-induced impairments of endocytosis and neurotransmission. We conclude that elevation of presynaptic WT tau induces de novo assembly of MTs, thereby sequestering free dynamins. As a result, endocytosis and subsequent vesicle replenishment are impaired, causing activity-dependent rundown of neurotransmission."}]},{"title":"Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 mice","date_updated":"2025-06-11T13:40:00Z","abstract":[{"lang":"eng","text":"Alzheimer’s disease (AD) is characterized by a reorganization of brain activity determining network hyperexcitability and loss of synaptic plasticity. Precisely, a dysfunction in metabotropic GABAB receptor signalling through G protein-gated inwardly rectifying K+ (GIRK or Kir3) channels on the hippocampus has been postulated. Thus, we determined the impact of amyloid-β (Aβ) pathology in GIRK channel density, subcellular distribution, and its association with GABAB receptors in hippocampal CA1 pyramidal neurons from the APP/PS1 mouse model using quantitative SDS-digested freeze-fracture replica labelling (SDS-FRL) and proximity ligation in situ assay (P-LISA). In wild type mice, single SDS-FRL detection revealed a similar dendritic gradient for GIRK1 and GIRK2 in CA1 pyramidal cells, with higher densities in spines, and GIRK3 showed a lower and uniform distribution. Double SDS-FRL showed a co-clustering of GIRK2 and GIRK1 in post- and presynaptic compartments, but not for GIRK2 and GIRK3. Likewise, double GABAB1 and GIRK2 SDS-FRL detection displayed a high degree of co-clustering in nanodomains (40–50 nm) mostly in spines and axon terminals. In APP/PS1 mice, the density of GIRK2 and GIRK1, but not for GIRK3, was significantly reduced along the neuronal surface of CA1 pyramidal cells and in axon terminals contacting them. Importantly, GABAB1 and GIRK2 co-clustering was not present in APP/PS1 mice. Similarly, P-LISA experiments revealed a significant reduction in GABAB1 and GIRK2 interaction on the hippocampus of this animal model. Overall, our results provide compelling evidence showing a significant reduction on the cell surface density of pre- and postsynaptic GIRK1 and GIRK2, but not GIRK3, and a decline in GABAB receptors and GIRK2 channels co-clustering in hippocampal pyramidal neurons from APP/PS1 mice, thus suggesting that a disruption in the GABAB receptor–GIRK channel membrane assembly causes dysregulation in the GABAB signalling via GIRK channels in this AD animal model."}],"author":[{"full_name":"Martín-Belmonte, Alejandro","first_name":"Alejandro","last_name":"Martín-Belmonte"},{"first_name":"Carolina","last_name":"Aguado","full_name":"Aguado, Carolina"},{"last_name":"Alfaro-Ruiz","first_name":"Rocío","full_name":"Alfaro-Ruiz, Rocío"},{"last_name":"Moreno-Martínez","first_name":"Ana Esther","full_name":"Moreno-Martínez, Ana Esther"},{"full_name":"de la Ossa, Luis","first_name":"Luis","last_name":"de la Ossa"},{"full_name":"Aso, Ester","first_name":"Ester","last_name":"Aso"},{"full_name":"Gómez-Acero, Laura","last_name":"Gómez-Acero","first_name":"Laura"},{"first_name":"Ryuichi","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","last_name":"Shigemoto","orcid":"0000-0001-8761-9444","full_name":"Shigemoto, Ryuichi"},{"last_name":"Fukazawa","first_name":"Yugo","full_name":"Fukazawa, Yugo"},{"full_name":"Ciruela, Francisco","last_name":"Ciruela","first_name":"Francisco"},{"last_name":"Luján","first_name":"Rafael","full_name":"Luján, Rafael"}],"article_number":"136","day":"21","volume":14,"citation":{"ama":"Martín-Belmonte A, Aguado C, Alfaro-Ruiz R, et al. Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 mice. <i>Alzheimer’s Research &#38; Therapy</i>. 2022;14. doi:<a href=\"https://doi.org/10.1186/s13195-022-01078-5\">10.1186/s13195-022-01078-5</a>","apa":"Martín-Belmonte, A., Aguado, C., Alfaro-Ruiz, R., Moreno-Martínez, A. E., de la Ossa, L., Aso, E., … Luján, R. (2022). Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 mice. <i>Alzheimer’s Research &#38; Therapy</i>. Springer Nature. <a href=\"https://doi.org/10.1186/s13195-022-01078-5\">https://doi.org/10.1186/s13195-022-01078-5</a>","ieee":"A. Martín-Belmonte <i>et al.</i>, “Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 mice,” <i>Alzheimer’s Research &#38; Therapy</i>, vol. 14. Springer Nature, 2022.","ista":"Martín-Belmonte A, Aguado C, Alfaro-Ruiz R, Moreno-Martínez AE, de la Ossa L, Aso E, Gómez-Acero L, Shigemoto R, Fukazawa Y, Ciruela F, Luján R. 2022. Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 mice. Alzheimer’s Research &#38; Therapy. 14, 136.","chicago":"Martín-Belmonte, Alejandro, Carolina Aguado, Rocío Alfaro-Ruiz, Ana Esther Moreno-Martínez, Luis de la Ossa, Ester Aso, Laura Gómez-Acero, et al. “Nanoscale Alterations in GABAB Receptors and GIRK Channel Organization on the Hippocampus of APP/PS1 Mice.” <i>Alzheimer’s Research &#38; Therapy</i>. Springer Nature, 2022. <a href=\"https://doi.org/10.1186/s13195-022-01078-5\">https://doi.org/10.1186/s13195-022-01078-5</a>.","short":"A. Martín-Belmonte, C. Aguado, R. Alfaro-Ruiz, A.E. Moreno-Martínez, L. de la Ossa, E. Aso, L. Gómez-Acero, R. Shigemoto, Y. Fukazawa, F. Ciruela, R. Luján, Alzheimer’s Research &#38; Therapy 14 (2022).","mla":"Martín-Belmonte, Alejandro, et al. “Nanoscale Alterations in GABAB Receptors and GIRK Channel Organization on the Hippocampus of APP/PS1 Mice.” <i>Alzheimer’s Research &#38; Therapy</i>, vol. 14, 136, Springer Nature, 2022, doi:<a href=\"https://doi.org/10.1186/s13195-022-01078-5\">10.1186/s13195-022-01078-5</a>."},"intvolume":"        14","acknowledgement":"We thank Ms. Diane Latawiec for the English revision of the manuscript. Funding sources were the Spanish Ministerio de Economía y Competitividad, Junta de Comunidades de Castilla-La Mancha (Spain), and Life Science Innovation Center at University of Fukui. We thank Centres de Recerca de Catalunya (CERCA) Programme/Generalitat de Catalunya for IDIBELL institutional support. We thank Hitoshi Takagi and Takako Maegawa at the University of Fukui for their technical assistance on SDS-FRL experiments.\r\nThis work was supported by grants from the Spanish Ministerio de Economía y Competitividad (BFU2015-63769-R, RTI2018-095812-B-I00, and PID2021-125875OB-I00) and Junta de Comunidades de Castilla-La Mancha (SBPLY/17/180501/000229 and SBPLY/21/180501/000064) to RL, Life Science Innovation Center at University of Fukui and JSPS KAKENHI (Grant Numbers 16H04662, 19H03323, and 20H05058) to YF, and Margarita Salas fellowship from Ministerio de Universidades and Universidad de Castilla-La Mancha to AMB.","external_id":{"pmid":["36131327"],"isi":["000857985500001"]},"oa":1,"article_type":"original","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)"},"article_processing_charge":"No","date_created":"2023-01-16T09:45:51Z","year":"2022","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publication_status":"published","language":[{"iso":"eng"}],"publication":"Alzheimer's Research & Therapy","type":"journal_article","publisher":"Springer Nature","ddc":["570"],"month":"09","_id":"12212","scopus_import":"1","oa_version":"Published Version","isi":1,"date_published":"2022-09-21T00:00:00Z","has_accepted_license":"1","pmid":1,"file_date_updated":"2023-01-27T07:53:18Z","status":"public","keyword":["Cognitive Neuroscience","Neurology (clinical)","Neurology"],"quality_controlled":"1","file":[{"access_level":"open_access","creator":"dernst","date_updated":"2023-01-27T07:53:18Z","file_id":"12413","checksum":"88e49715ad6a1abf0fdb27efd65368dc","file_size":11013325,"file_name":"2022_AlzheimersResearch_MartinBelmont.pdf","success":1,"relation":"main_file","date_created":"2023-01-27T07:53:18Z","content_type":"application/pdf"}],"publication_identifier":{"issn":["1758-9193"]},"doi":"10.1186/s13195-022-01078-5","fulldoi":"https://doi.org/10.1186/s13195-022-01078-5","department":[{"_id":"RySh"}]}]