[{"article_processing_charge":"No","type":"dissertation","date_created":"2022-05-17T08:57:41Z","day":"16","date_updated":"2026-04-07T14:31:19Z","abstract":[{"text":"AMPA receptors (AMPARs) mediate fast excitatory neurotransmission and their role is\r\nimplicated in complex processes such as learning and memory and various neurological\r\ndiseases. These receptors are composed of different subunits and the subunit composition can\r\naffect channel properties, receptor trafficking and interaction with other associated proteins.\r\nUsing the high sensitivity SDS-digested freeze-fracture replica labeling (SDS-FRL) for\r\nelectron microscopy I investigated the number, density, and localization of AMPAR subunits,\r\nGluA1, GluA2, GluA3, and GluA1-3 (panAMPA) in pyramidal cells in the CA1 area of mouse\r\nhippocampus. I have found that the immunogold labeling for all of these subunits in the\r\npostsynaptic sites was highest in stratum radiatum and lowest in stratum lacunosummoleculare. The labeling density for the all subunits in the extrasynaptic sites showed a gradual\r\nincrease from the pyramidal cell soma towards the distal part of stratum radiatum. The densities\r\nof extrasynaptic GluA1, GluA2 and panAMPA labeling reached 10-15% of synaptic densities,\r\nwhile the ratio of extrasynaptic labeling for GluA3 was significantly lower compared than those\r\nfor other subunits. The labeling patterns for GluA1, GluA2 and GluA1-3 are similar and their\r\ndensities were higher in the periphery than center of synapses. In contrast, the GluA3-\r\ncontaining receptors were more centrally localized compared to the GluA1- and GluA2-\r\ncontaining receptors.\r\nThe hippocampus plays a central role in learning and memory. Contextual learning has been\r\nshown to require the delivery of AMPA receptors to CA1 synapses in the dorsal hippocampus.\r\nHowever, proximodistal heterogeneity of this plasticity and particular contribution of different\r\nAMPA receptor subunits are not fully understood. By combining inhibitory avoidance task, a\r\nhippocampus-dependent contextual fear-learning paradigm, with SDS-FRL, I have revealed an\r\nincrease in synaptic density specific to GluA1-containing AMPA receptors in the CA1 area.\r\nThe intrasynaptic distribution of GluA1 also changed from the periphery to center-preferred\r\npattern. Furthermore, this synaptic plasticity was evident selectively in stratum radiatum but\r\nnot stratum oriens, and in the CA1 subregion proximal but not distal to CA2. These findings\r\nfurther contribute to our understanding of how specific hippocampal subregions and AMPA\r\nreceptor subunits are involved in physiological learning.\r\nAlthough the immunolabeling results above shed light on subunit-specific plasticity in\r\nAMPAR distribution, no tools to visualize and study the subunit composition at the single\r\nchannel level in situ have been available. Electron microscopy with conventional immunogold\r\nlabeling approaches has limitations in the single channel analysis because of the large size of\r\nantibodies and steric hindrance hampering multiple subunit labeling of single channels. I\r\nmanaged to develop a new chemical labeling system using a short peptide tag and small\r\nsynthetic probes, which form specific covalent bond with a cysteine residue in the tag fused to\r\nproteins of interest (reactive tag system). I additionally made substantial progress into adapting\r\nthis system for AMPA receptor subunits.","lang":"eng"}],"fulldoi":"https://doi.org/10.15479/at:ista:11393","acknowledged_ssus":[{"_id":"EM-Fac"}],"month":"05","language":[{"iso":"eng"}],"has_accepted_license":"1","department":[{"_id":"GradSch"},{"_id":"RySh"}],"status":"public","oa_version":"Published Version","_id":"11393","author":[{"last_name":"Jevtic","id":"4BE3BC94-F248-11E8-B48F-1D18A9856A87","full_name":"Jevtic, Marijo","first_name":"Marijo"}],"file_date_updated":"2023-05-17T22:30:03Z","date_published":"2022-05-16T00:00:00Z","title":"Contextual fear learning induced changes in AMPA receptor subtypes along the proximodistal axis in dorsal hippocampus","publication_identifier":{"issn":["2663-337X"]},"ddc":["570"],"degree_awarded":"PhD","year":"2022","doi":"10.15479/at:ista:11393","page":"108","corr_author":"1","publication_status":"published","citation":{"chicago":"Jevtic, Marijo. “Contextual Fear Learning Induced Changes in AMPA Receptor Subtypes along the Proximodistal Axis in Dorsal Hippocampus.” Institute of Science and Technology Austria, 2022. <a href=\"https://doi.org/10.15479/at:ista:11393\">https://doi.org/10.15479/at:ista:11393</a>.","mla":"Jevtic, Marijo. <i>Contextual Fear Learning Induced Changes in AMPA Receptor Subtypes along the Proximodistal Axis in Dorsal Hippocampus</i>. Institute of Science and Technology Austria, 2022, doi:<a href=\"https://doi.org/10.15479/at:ista:11393\">10.15479/at:ista:11393</a>.","ista":"Jevtic M. 2022. Contextual fear learning induced changes in AMPA receptor subtypes along the proximodistal axis in dorsal hippocampus. Institute of Science and Technology Austria.","ieee":"M. Jevtic, “Contextual fear learning induced changes in AMPA receptor subtypes along the proximodistal axis in dorsal hippocampus,” Institute of Science and Technology Austria, 2022.","apa":"Jevtic, M. (2022). <i>Contextual fear learning induced changes in AMPA receptor subtypes along the proximodistal axis in dorsal hippocampus</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/at:ista:11393\">https://doi.org/10.15479/at:ista:11393</a>","ama":"Jevtic M. Contextual fear learning induced changes in AMPA receptor subtypes along the proximodistal axis in dorsal hippocampus. 2022. doi:<a href=\"https://doi.org/10.15479/at:ista:11393\">10.15479/at:ista:11393</a>","short":"M. Jevtic, Contextual Fear Learning Induced Changes in AMPA Receptor Subtypes along the Proximodistal Axis in Dorsal Hippocampus, Institute of Science and Technology Austria, 2022."},"user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","supervisor":[{"last_name":"Shigemoto","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","first_name":"Ryuichi","full_name":"Shigemoto, Ryuichi","orcid":"0000-0001-8761-9444"}],"related_material":{"record":[{"id":"7391","relation":"part_of_dissertation","status":"public"}]},"oa":1,"OA_place":"publisher","alternative_title":["ISTA Thesis"],"file":[{"relation":"source_file","file_size":56427603,"content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document","date_created":"2022-05-17T09:08:06Z","embargo_to":"open_access","date_updated":"2023-05-17T22:30:03Z","file_name":"MJ thesis.docx","access_level":"closed","creator":"cchlebak","checksum":"8fc695d88020d70d231dad0e9f10b138","file_id":"11395"},{"date_created":"2022-05-17T12:09:25Z","embargo":"2023-05-16","content_type":"application/pdf","relation":"main_file","file_size":4351981,"checksum":"c1dd20a1aece521b3500607b00e463d6","file_id":"11397","creator":"cchlebak","access_level":"open_access","file_name":"MJ_thesis_PDFA.pdf","date_updated":"2023-05-17T22:30:03Z"}],"publisher":"Institute of Science and Technology Austria"},{"oa_version":"Published Version","acknowledgement":"This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through the Collaborative Sensory Research Center 1286 [to C.W. (A4) and T.M. (B5)] and under Germany’s Excellence Strategy Grant EXC 2067/1-390729940. We thank S. Gerke, A.J. Goldak, and C. Senger-Freitag for expert technical assistance; G. Hoch for developing image analysis routines; and S. Chepurwar and N. Strenzke for technical support and discussion regarding in vivo experiments. We also thank Dr. Christian Rosenmund, Dr. Katharina Grauel, and Dr. Stephan Sigrist for providing RIM-BP2 KO mice and Dr. Masahiko Watanabe for providing the anti-neurexin-antibody, and Dr. Toshihisa Ohtsuka for the anti-ELKS-antibody. J. Neef for help with the STED imaging and image analysis; E. Neher and S. Rizzoli for discussion and comments on the manuscript; K. Eguchi for help with the statistical analysis; and C. H. Huang and J. Neef for constant support and scientific discussion.","_id":"10051","external_id":{"pmid":["34353898"],"isi":["000752287700005"]},"author":[{"first_name":"Tanvi","full_name":"Butola, Tanvi","last_name":"Butola"},{"last_name":"Alvanos","first_name":"Theocharis","full_name":"Alvanos, Theocharis"},{"last_name":"Hintze","first_name":"Anika","full_name":"Hintze, Anika"},{"orcid":"0000-0002-3509-1948","id":"3B8B25A8-F248-11E8-B48F-1D18A9856A87","full_name":"Koppensteiner, Peter","first_name":"Peter","last_name":"Koppensteiner"},{"full_name":"Kleindienst, David","id":"42E121A4-F248-11E8-B48F-1D18A9856A87","last_name":"Kleindienst","first_name":"David"},{"orcid":"0000-0001-8761-9444","last_name":"Shigemoto","full_name":"Shigemoto, Ryuichi","first_name":"Ryuichi","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Wichmann, Carolin","first_name":"Carolin","last_name":"Wichmann"},{"last_name":"Moser","full_name":"Moser, Tobias","first_name":"Tobias"}],"scopus_import":"1","publication":"Journal of Neuroscience","file_date_updated":"2022-05-31T09:10:15Z","date_published":"2021-09-15T00:00:00Z","title":"RIM-binding protein 2 organizes Ca<sup>21</sup> channel topography and regulates release probability and vesicle replenishment at a fast central synapse","publication_identifier":{"eissn":["1529-2401"],"issn":["0270-6474"]},"type":"journal_article","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"article_processing_charge":"No","volume":41,"date_created":"2021-09-27T14:33:13Z","date_updated":"2023-08-14T06:56:30Z","day":"15","abstract":[{"lang":"eng","text":"Rab-interacting molecule (RIM)-binding protein 2 (BP2) is a multidomain protein of the presynaptic active zone (AZ). By binding to RIM, bassoon (Bsn), and voltage-gated Ca2+ channels (CaV), it is considered to be a central organizer of the topography of CaV and release sites of synaptic vesicles (SVs) at the AZ. Here, we used RIM-BP2 knock-out (KO) mice and their wild-type (WT) littermates of either sex to investigate the role of RIM-BP2 at the endbulb of Held synapse of auditory nerve fibers (ANFs) with bushy cells (BCs) of the cochlear nucleus, a fast relay of the auditory pathway with high release probability. Disruption of RIM-BP2 lowered release probability altering short-term plasticity and reduced evoked EPSCs. Analysis of SV pool dynamics during high-frequency train stimulation indicated a reduction of SVs with high release probability but an overall normal size of the readily releasable SV pool (RRP). The Ca2+-dependent fast component of SV replenishment after RRP depletion was slowed. Ultrastructural analysis by superresolution light and electron microscopy revealed an impaired topography of presynaptic CaV and a reduction of docked and membrane-proximal SVs at the AZ. We conclude that RIM-BP2 organizes the topography of CaV, and promotes SV tethering and docking. This way RIM-BP2 is critical for establishing a high initial release probability as required to reliably signal sound onset information that we found to be degraded in BCs of RIM-BP2-deficient mice in vivo. SIGNIFICANCE STATEMENT: Rab-interacting molecule (RIM)-binding proteins (BPs) are key organizers of the active zone (AZ). Using a multidisciplinary approach to the calyceal endbulb of Held synapse that transmits auditory information at rates of up to hundreds of Hertz with submillisecond precision we demonstrate a requirement for RIM-BP2 for normal auditory signaling. Endbulb synapses lacking RIM-BP2 show a reduced release probability despite normal whole-terminal Ca2+ influx and abundance of the key priming protein Munc13-1, a reduced rate of SV replenishment, as well as an altered topography of voltage-gated (CaV)2.1 Ca2+ channels, and fewer docked and membrane proximal synaptic vesicles (SVs). This hampers transmission of sound onset information likely affecting downstream neural computations such as of sound localization."}],"fulldoi":"https://doi.org/10.1523/JNEUROSCI.0586-21.2021","month":"09","language":[{"iso":"eng"}],"has_accepted_license":"1","department":[{"_id":"RySh"}],"status":"public","oa":1,"isi":1,"article_type":"original","pmid":1,"file":[{"content_type":"application/pdf","file_size":11571961,"relation":"main_file","date_created":"2022-05-31T09:10:15Z","file_name":"2021_JourNeuroscience_Butola.pdf","date_updated":"2022-05-31T09:10:15Z","checksum":"769ab627c7355a50ccfd445e43a5f351","file_id":"11423","success":1,"access_level":"open_access","creator":"dernst"}],"intvolume":"        41","issue":"37","publisher":"Society for Neuroscience","ddc":["570"],"quality_controlled":"1","year":"2021","doi":"10.1523/JNEUROSCI.0586-21.2021","page":"7742-7767","publication_status":"published","citation":{"short":"T. Butola, T. Alvanos, A. Hintze, P. Koppensteiner, D. Kleindienst, R. Shigemoto, C. Wichmann, T. Moser, Journal of Neuroscience 41 (2021) 7742–7767.","ama":"Butola T, Alvanos T, Hintze A, et al. RIM-binding protein 2 organizes Ca<sup>21</sup> channel topography and regulates release probability and vesicle replenishment at a fast central synapse. <i>Journal of Neuroscience</i>. 2021;41(37):7742-7767. doi:<a href=\"https://doi.org/10.1523/JNEUROSCI.0586-21.2021\">10.1523/JNEUROSCI.0586-21.2021</a>","chicago":"Butola, Tanvi, Theocharis Alvanos, Anika Hintze, Peter Koppensteiner, David Kleindienst, Ryuichi Shigemoto, Carolin Wichmann, and Tobias Moser. “RIM-Binding Protein 2 Organizes Ca<sup>21</sup> Channel Topography and Regulates Release Probability and Vesicle Replenishment at a Fast Central Synapse.” <i>Journal of Neuroscience</i>. Society for Neuroscience, 2021. <a href=\"https://doi.org/10.1523/JNEUROSCI.0586-21.2021\">https://doi.org/10.1523/JNEUROSCI.0586-21.2021</a>.","mla":"Butola, Tanvi, et al. “RIM-Binding Protein 2 Organizes Ca<sup>21</sup> Channel Topography and Regulates Release Probability and Vesicle Replenishment at a Fast Central Synapse.” <i>Journal of Neuroscience</i>, vol. 41, no. 37, Society for Neuroscience, 2021, pp. 7742–67, doi:<a href=\"https://doi.org/10.1523/JNEUROSCI.0586-21.2021\">10.1523/JNEUROSCI.0586-21.2021</a>.","ista":"Butola T, Alvanos T, Hintze A, Koppensteiner P, Kleindienst D, Shigemoto R, Wichmann C, Moser T. 2021. RIM-binding protein 2 organizes Ca<sup>21</sup> channel topography and regulates release probability and vesicle replenishment at a fast central synapse. Journal of Neuroscience. 41(37), 7742–7767.","apa":"Butola, T., Alvanos, T., Hintze, A., Koppensteiner, P., Kleindienst, D., Shigemoto, R., … Moser, T. (2021). RIM-binding protein 2 organizes Ca<sup>21</sup> channel topography and regulates release probability and vesicle replenishment at a fast central synapse. <i>Journal of Neuroscience</i>. Society for Neuroscience. <a href=\"https://doi.org/10.1523/JNEUROSCI.0586-21.2021\">https://doi.org/10.1523/JNEUROSCI.0586-21.2021</a>","ieee":"T. Butola <i>et al.</i>, “RIM-binding protein 2 organizes Ca<sup>21</sup> channel topography and regulates release probability and vesicle replenishment at a fast central synapse,” <i>Journal of Neuroscience</i>, vol. 41, no. 37. Society for Neuroscience, pp. 7742–7767, 2021."},"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8"},{"volume":10,"date_created":"2021-12-05T23:01:40Z","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"type":"journal_article","article_processing_charge":"No","department":[{"_id":"RySh"}],"status":"public","has_accepted_license":"1","month":"11","language":[{"iso":"eng"}],"fulldoi":"https://doi.org/10.7554/eLife.65954","abstract":[{"text":"Synaptic transmission, connectivity, and dendritic morphology mature in parallel during brain development and are often disrupted in neurodevelopmental disorders. Yet how these changes influence the neuronal computations necessary for normal brain function are not well understood. To identify cellular mechanisms underlying the maturation of synaptic integration in interneurons, we combined patch-clamp recordings of excitatory inputs in mouse cerebellar stellate cells (SCs), three-dimensional reconstruction of SC morphology with excitatory synapse location, and biophysical modeling. We found that postnatal maturation of postsynaptic strength was homogeneously reduced along the somatodendritic axis, but dendritic integration was always sublinear. However, dendritic branching increased without changes in synapse density, leading to a substantial gain in distal inputs. Thus, changes in synapse distribution, rather than dendrite cable properties, are the dominant mechanism underlying the maturation of neuronal computation. These mechanisms favor the emergence of a spatially compartmentalized two-stage integration model promoting location-dependent integration within dendritic subunits.","lang":"eng"}],"day":"03","date_updated":"2025-03-07T08:12:39Z","author":[{"first_name":"Celia","full_name":"Biane, Celia","last_name":"Biane"},{"full_name":"Rückerl, Florian","first_name":"Florian","last_name":"Rückerl"},{"full_name":"Abrahamsson, Therese","last_name":"Abrahamsson","first_name":"Therese"},{"full_name":"Saint-Cloment, Cécile","first_name":"Cécile","last_name":"Saint-Cloment"},{"first_name":"Jean","full_name":"Mariani, Jean","last_name":"Mariani"},{"full_name":"Shigemoto, Ryuichi","last_name":"Shigemoto","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","first_name":"Ryuichi","orcid":"0000-0001-8761-9444"},{"first_name":"David A.","last_name":"Digregorio","full_name":"Digregorio, David A."},{"first_name":"Rachel M.","full_name":"Sherrard, Rachel M.","last_name":"Sherrard"},{"full_name":"Cathala, Laurence","first_name":"Laurence","last_name":"Cathala"}],"publication":"eLife","scopus_import":"1","external_id":{"isi":["000715789500001"],"pmid":["34730085"]},"_id":"10403","acknowledgement":"This study was supported by the Centre National de la Recherche Scientifique and the Agence Nationale de la Recherche (ANR-13-BSV4-00166, to LC and DAD). TA was supported by fellowships from the Fondation pour la Recherche Medicale and the Swedish Research Council. We thank Dmitry Ershov from the Image Analysis Hub of the Institut Pasteur, Elodie Le Monnier, Elena Hollergschwandtner, Vanessa Zheden, and Corinne Nantet for technical support and Haining Zhong for providing the Venus-tagged PSD95 mouse line. We would like to thank Alberto Bacci, Ann Lohof, and Nelson Rebola for comments on the manuscript.","oa_version":"Published Version","publication_identifier":{"eissn":["2050-084X"]},"title":"Developmental emergence of two-stage nonlinear synaptic integration in cerebellar interneurons","date_published":"2021-11-03T00:00:00Z","file_date_updated":"2021-12-10T08:31:41Z","doi":"10.7554/eLife.65954","year":"2021","quality_controlled":"1","ddc":["570"],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","citation":{"chicago":"Biane, Celia, Florian Rückerl, Therese Abrahamsson, Cécile Saint-Cloment, Jean Mariani, Ryuichi Shigemoto, David A. Digregorio, Rachel M. Sherrard, and Laurence Cathala. “Developmental Emergence of Two-Stage Nonlinear Synaptic Integration in Cerebellar Interneurons.” <i>ELife</i>. eLife Sciences Publications, 2021. <a href=\"https://doi.org/10.7554/eLife.65954\">https://doi.org/10.7554/eLife.65954</a>.","mla":"Biane, Celia, et al. “Developmental Emergence of Two-Stage Nonlinear Synaptic Integration in Cerebellar Interneurons.” <i>ELife</i>, vol. 10, e65954, eLife Sciences Publications, 2021, doi:<a href=\"https://doi.org/10.7554/eLife.65954\">10.7554/eLife.65954</a>.","ista":"Biane C, Rückerl F, Abrahamsson T, Saint-Cloment C, Mariani J, Shigemoto R, Digregorio DA, Sherrard RM, Cathala L. 2021. Developmental emergence of two-stage nonlinear synaptic integration in cerebellar interneurons. eLife. 10, e65954.","apa":"Biane, C., Rückerl, F., Abrahamsson, T., Saint-Cloment, C., Mariani, J., Shigemoto, R., … Cathala, L. (2021). Developmental emergence of two-stage nonlinear synaptic integration in cerebellar interneurons. <i>ELife</i>. eLife Sciences Publications. <a href=\"https://doi.org/10.7554/eLife.65954\">https://doi.org/10.7554/eLife.65954</a>","ieee":"C. Biane <i>et al.</i>, “Developmental emergence of two-stage nonlinear synaptic integration in cerebellar interneurons,” <i>eLife</i>, vol. 10. eLife Sciences Publications, 2021.","short":"C. Biane, F. Rückerl, T. Abrahamsson, C. Saint-Cloment, J. Mariani, R. Shigemoto, D.A. Digregorio, R.M. Sherrard, L. Cathala, ELife 10 (2021).","ama":"Biane C, Rückerl F, Abrahamsson T, et al. Developmental emergence of two-stage nonlinear synaptic integration in cerebellar interneurons. <i>eLife</i>. 2021;10. doi:<a href=\"https://doi.org/10.7554/eLife.65954\">10.7554/eLife.65954</a>"},"publication_status":"published","pmid":1,"article_number":"e65954","article_type":"original","isi":1,"oa":1,"publisher":"eLife Sciences Publications","intvolume":"        10","file":[{"content_type":"application/pdf","file_size":13131322,"relation":"main_file","date_created":"2021-12-10T08:31:41Z","file_name":"2021_eLife_Biane.pdf","date_updated":"2021-12-10T08:31:41Z","checksum":"c7c33c3319428d56e332e22349c50ed3","file_id":"10528","success":1,"creator":"cchlebak","access_level":"open_access"}]},{"article_processing_charge":"No","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"type":"journal_article","volume":118,"date_created":"2021-04-18T22:01:40Z","fulldoi":"https://doi.org/10.1073/pnas.1920827118","abstract":[{"lang":"eng","text":"In nerve cells the genes encoding for α2δ subunits of voltage-gated calcium channels have been linked to synaptic functions and neurological disease. Here we show that α2δ subunits are essential for the formation and organization of glutamatergic synapses. Using a cellular α2δ subunit triple-knockout/knockdown model, we demonstrate a failure in presynaptic differentiation evidenced by defective presynaptic calcium channel clustering and calcium influx, smaller presynaptic active zones, and a strongly reduced accumulation of presynaptic vesicle-associated proteins (synapsin and vGLUT). The presynaptic defect is associated with the downscaling of postsynaptic AMPA receptors and the postsynaptic density. The role of α2δ isoforms as synaptic organizers is highly redundant, as each individual α2δ isoform can rescue presynaptic calcium channel trafficking and expression of synaptic proteins. Moreover, α2δ-2 and α2δ-3 with mutated metal ion-dependent adhesion sites can fully rescue presynaptic synapsin expression but only partially calcium channel trafficking, suggesting that the regulatory role of α2δ subunits is independent from its role as a calcium channel subunit. Our findings influence the current view on excitatory synapse formation. First, our study suggests that postsynaptic differentiation is secondary to presynaptic differentiation. Second, the dependence of presynaptic differentiation on α2δ implicates α2δ subunits as potential nucleation points for the organization of synapses. Finally, our results suggest that α2δ subunits act as transsynaptic organizers of glutamatergic synapses, thereby aligning the synaptic active zone with the postsynaptic density."}],"day":"06","date_updated":"2025-06-12T06:56:21Z","status":"public","department":[{"_id":"EM-Fac"},{"_id":"RySh"}],"has_accepted_license":"1","month":"04","language":[{"iso":"eng"}],"acknowledged_ssus":[{"_id":"EM-Fac"}],"_id":"9330","acknowledgement":"We thank Arnold Schwartz for providing α2δ-1 knockout mice; Ariane Benedetti, Sabine Baumgartner, Sandra Demetz, and Irene Mahlknecht for technical support; Nadine Ortner and Andreas Lieb for electrophysiological experiments; the team of the Electron Microscopy Facility at the Institute of Science and Technology Austria for technical support related to ultrastructural analysis; Hermann Dietrich and Anja Beierfuß and her team for animal care; Jutta Engel and Jörg Striessnig for critical discussions; and Bruno Benedetti and Bernhard Flucher for critical discussions and reading the manuscript. This study was supported by Austrian Science Fund Grants P24079, F44060, F44150, and DOC30-B30 (to G.J.O.) and T855 (to M.C.), European Research Council Grant AdG 694539 (to R.S.), Deutsche Forschungsgemeinschaft\r\nGrant SFB1348-TP A03 (to M.M.), and Interdisziplinäre Zentrum für Klinische Forschung Münster Grant Mi3/004/19 (to M.M.). This work is part of the PhD theses of C.L.S., S.M.G., and C.A.","oa_version":"Published Version","scopus_import":"1","author":[{"last_name":"Schöpf","full_name":"Schöpf, Clemens L.","first_name":"Clemens L."},{"last_name":"Ablinger","full_name":"Ablinger, Cornelia","first_name":"Cornelia"},{"first_name":"Stefanie M.","full_name":"Geisler, Stefanie M.","last_name":"Geisler"},{"full_name":"Stanika, Ruslan I.","last_name":"Stanika","first_name":"Ruslan I."},{"last_name":"Campiglio","full_name":"Campiglio, Marta","first_name":"Marta"},{"id":"3F99E422-F248-11E8-B48F-1D18A9856A87","first_name":"Walter","full_name":"Kaufmann, Walter","last_name":"Kaufmann","orcid":"0000-0001-9735-5315"},{"full_name":"Nimmervoll, Benedikt","last_name":"Nimmervoll","first_name":"Benedikt"},{"last_name":"Schlick","full_name":"Schlick, Bettina","first_name":"Bettina"},{"first_name":"Johannes","full_name":"Brockhaus, Johannes","last_name":"Brockhaus"},{"full_name":"Missler, Markus","last_name":"Missler","first_name":"Markus"},{"orcid":"0000-0001-8761-9444","full_name":"Shigemoto, Ryuichi","first_name":"Ryuichi","last_name":"Shigemoto","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Obermair, Gerald J.","first_name":"Gerald J.","last_name":"Obermair"}],"publication":"Proceedings of the National Academy of Sciences of the United States of America","external_id":{"isi":["000637398300002"],"pmid":["33782113"]},"date_published":"2021-04-06T00:00:00Z","file_date_updated":"2021-04-19T10:10:56Z","publication_identifier":{"eissn":["1091-6490"]},"title":"Presynaptic α2δ subunits are key organizers of glutamatergic synapses","quality_controlled":"1","ddc":["570"],"ec_funded":1,"year":"2021","doi":"10.1073/pnas.1920827118","citation":{"mla":"Schöpf, Clemens L., et al. “Presynaptic Α2δ Subunits Are Key Organizers of Glutamatergic Synapses.” <i>Proceedings of the National Academy of Sciences of the United States of America</i>, vol. 118, no. 14, National Academy of Sciences, 2021, doi:<a href=\"https://doi.org/10.1073/pnas.1920827118\">10.1073/pnas.1920827118</a>.","chicago":"Schöpf, Clemens L., Cornelia Ablinger, Stefanie M. Geisler, Ruslan I. Stanika, Marta Campiglio, Walter Kaufmann, Benedikt Nimmervoll, et al. “Presynaptic Α2δ Subunits Are Key Organizers of Glutamatergic Synapses.” <i>Proceedings of the National Academy of Sciences of the United States of America</i>. National Academy of Sciences, 2021. <a href=\"https://doi.org/10.1073/pnas.1920827118\">https://doi.org/10.1073/pnas.1920827118</a>.","apa":"Schöpf, C. L., Ablinger, C., Geisler, S. M., Stanika, R. I., Campiglio, M., Kaufmann, W., … Obermair, G. J. (2021). Presynaptic α2δ subunits are key organizers of glutamatergic synapses. <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.1920827118\">https://doi.org/10.1073/pnas.1920827118</a>","ieee":"C. L. Schöpf <i>et al.</i>, “Presynaptic α2δ subunits are key organizers of glutamatergic synapses,” <i>Proceedings of the National Academy of Sciences of the United States of America</i>, vol. 118, no. 14. National Academy of Sciences, 2021.","ista":"Schöpf CL, Ablinger C, Geisler SM, Stanika RI, Campiglio M, Kaufmann W, Nimmervoll B, Schlick B, Brockhaus J, Missler M, Shigemoto R, Obermair GJ. 2021. Presynaptic α2δ subunits are key organizers of glutamatergic synapses. Proceedings of the National Academy of Sciences of the United States of America. 118(14).","short":"C.L. Schöpf, C. Ablinger, S.M. Geisler, R.I. Stanika, M. Campiglio, W. Kaufmann, B. Nimmervoll, B. Schlick, J. Brockhaus, M. Missler, R. Shigemoto, G.J. Obermair, Proceedings of the National Academy of Sciences of the United States of America 118 (2021).","ama":"Schöpf CL, Ablinger C, Geisler SM, et al. Presynaptic α2δ subunits are key organizers of glutamatergic synapses. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. 2021;118(14). doi:<a href=\"https://doi.org/10.1073/pnas.1920827118\">10.1073/pnas.1920827118</a>"},"publication_status":"published","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","isi":1,"oa":1,"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"}],"pmid":1,"article_type":"original","file":[{"date_created":"2021-04-19T10:10:56Z","content_type":"application/pdf","relation":"main_file","file_size":2603911,"file_id":"9340","checksum":"dd014f68ae9d7d8d8fc4139a24e04506","creator":"dernst","access_level":"open_access","success":1,"file_name":"2021_PNAS_Schoepf.pdf","date_updated":"2021-04-19T10:10:56Z"}],"publisher":"National Academy of Sciences","issue":"14","intvolume":"       118"},{"ddc":["610"],"quality_controlled":"1","doi":"10.1016/j.nlm.2021.107486","year":"2021","ec_funded":1,"publication_status":"published","citation":{"short":"F. Fredes, R. Shigemoto, Neurobiology of Learning and Memory 183 (2021).","ama":"Fredes F, Shigemoto R. The role of hippocampal mossy cells in novelty detection. <i>Neurobiology of Learning and Memory</i>. 2021;183. doi:<a href=\"https://doi.org/10.1016/j.nlm.2021.107486\">10.1016/j.nlm.2021.107486</a>","chicago":"Fredes, Felipe, and Ryuichi Shigemoto. “The Role of Hippocampal Mossy Cells in Novelty Detection.” <i>Neurobiology of Learning and Memory</i>. Elsevier, 2021. <a href=\"https://doi.org/10.1016/j.nlm.2021.107486\">https://doi.org/10.1016/j.nlm.2021.107486</a>.","mla":"Fredes, Felipe, and Ryuichi Shigemoto. “The Role of Hippocampal Mossy Cells in Novelty Detection.” <i>Neurobiology of Learning and Memory</i>, vol. 183, 107486, Elsevier, 2021, doi:<a href=\"https://doi.org/10.1016/j.nlm.2021.107486\">10.1016/j.nlm.2021.107486</a>.","ista":"Fredes F, Shigemoto R. 2021. The role of hippocampal mossy cells in novelty detection. Neurobiology of Learning and Memory. 183, 107486.","apa":"Fredes, F., &#38; Shigemoto, R. (2021). The role of hippocampal mossy cells in novelty detection. <i>Neurobiology of Learning and Memory</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.nlm.2021.107486\">https://doi.org/10.1016/j.nlm.2021.107486</a>","ieee":"F. Fredes and R. Shigemoto, “The role of hippocampal mossy cells in novelty detection,” <i>Neurobiology of Learning and Memory</i>, vol. 183. Elsevier, 2021."},"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","project":[{"name":"In situ analysis of single channel subunit composition in neurons: physiological implication in synaptic plasticity and behaviour","grant_number":"694539","_id":"25CA28EA-B435-11E9-9278-68D0E5697425","call_identifier":"H2020"}],"oa":1,"isi":1,"article_type":"original","article_number":"107486","pmid":1,"file":[{"date_created":"2021-07-19T13:46:06Z","relation":"main_file","file_size":1994793,"content_type":"application/pdf","creator":"cziletti","access_level":"open_access","success":1,"file_id":"9694","checksum":"8e8298a9e8c7df146ad23f32c2a63929","date_updated":"2021-07-19T13:46:06Z","file_name":"2021_NeurobLearnMemory_Fredes.pdf"}],"intvolume":"       183","publisher":"Elsevier","type":"journal_article","tmp":{"name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","image":"/images/cc_by_nc_nd.png","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","short":"CC BY-NC-ND (4.0)"},"article_processing_charge":"No","volume":183,"date_created":"2021-07-11T22:01:16Z","day":"30","date_updated":"2025-07-10T12:02:00Z","abstract":[{"lang":"eng","text":"At the encounter with a novel environment, contextual memory formation is greatly enhanced, accompanied with increased arousal and active exploration. Although this phenomenon has been widely observed in animal and human daily life, how the novelty in the environment is detected and contributes to contextual memory formation has lately started to be unveiled. The hippocampus has been studied for many decades for its largely known roles in encoding spatial memory, and a growing body of evidence indicates a differential involvement of dorsal and ventral hippocampal divisions in novelty detection. In this brief review article, we discuss the recent findings of the role of mossy cells in the ventral hippocampal moiety in novelty detection and put them in perspective with other novelty-related pathways in the hippocampus. We propose a mechanism for novelty-driven memory acquisition in the dentate gyrus by the direct projection of ventral mossy cells to dorsal dentate granule cells. By this projection, the ventral hippocampus sends novelty signals to the dorsal hippocampus, opening a gate for memory encoding in dentate granule cells based on information coming from the entorhinal cortex. We conclude that, contrary to the presently accepted functional independence, the dorsal and ventral hippocampi cooperate to link the novelty and contextual information, and this dorso-ventral interaction is crucial for the novelty-dependent memory formation."}],"fulldoi":"https://doi.org/10.1016/j.nlm.2021.107486","language":[{"iso":"eng"}],"month":"06","has_accepted_license":"1","department":[{"_id":"RySh"}],"status":"public","oa_version":"Published Version","acknowledgement":"This work was supported by a European Research Council Advanced Grant 694539 to Ryuichi Shigemoto.","_id":"9641","external_id":{"pmid":["34214666"],"isi":["000677694900004"]},"publication":"Neurobiology of Learning and Memory","author":[{"full_name":"Fredes, Felipe","last_name":"Fredes","first_name":"Felipe"},{"id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","full_name":"Shigemoto, Ryuichi","first_name":"Ryuichi","last_name":"Shigemoto","orcid":"0000-0001-8761-9444"}],"scopus_import":"1","file_date_updated":"2021-07-19T13:46:06Z","date_published":"2021-06-30T00:00:00Z","title":"The role of hippocampal mossy cells in novelty detection","publication_identifier":{"eissn":["1095-9564"],"issn":["1074-7427"]}},{"title":"Ventro-dorsal hippocampal pathway gates novelty-induced contextual memory formation","file_date_updated":"2020-10-19T13:31:28Z","date_published":"2021-01-11T00:00:00Z","external_id":{"isi":["000614361000020"],"pmid":["33065009"]},"author":[{"id":"384825DA-F248-11E8-B48F-1D18A9856A87","last_name":"Fredes Tolorza","full_name":"Fredes Tolorza, Felipe A","first_name":"Felipe A"},{"id":"371B3D6E-F248-11E8-B48F-1D18A9856A87","last_name":"Silva Sifuentes","first_name":"Maria A","full_name":"Silva Sifuentes, Maria A"},{"id":"3B8B25A8-F248-11E8-B48F-1D18A9856A87","first_name":"Peter","last_name":"Koppensteiner","full_name":"Koppensteiner, Peter","orcid":"0000-0002-3509-1948"},{"full_name":"Kobayashi, Kenta","last_name":"Kobayashi","first_name":"Kenta"},{"id":"2BD278E6-F248-11E8-B48F-1D18A9856A87","full_name":"Jösch, Maximilian A","last_name":"Jösch","first_name":"Maximilian A","orcid":"0000-0002-3937-1330"},{"orcid":"0000-0001-8761-9444","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","full_name":"Shigemoto, Ryuichi","last_name":"Shigemoto","first_name":"Ryuichi"}],"scopus_import":"1","publication":"Current Biology","acknowledgement":"We thank Peter Jonas and Peter Somogyi for critically reading the manuscript, Satoshi Kida for helpful discussion, Taijia Makinen for providing the Prox1-creERT2 mouse line, and Hiromu Yawo for the VAMP2-Venus construct. We also thank Vivek Jayaraman, Ph.D.; Rex A. Kerr, Ph.D.; Douglas S. Kim, Ph.D.; Loren L. Looger, Ph.D.; and Karel Svoboda, Ph.D. from the GENIE Project, Janelia Farm Research Campus, Howard Hughes Medical Institute for the viral constructs used for GCaMP6s expression. We also thank Jacqueline Montanaro, Vanessa Zheden, David Kleindienst, and Laura Burnett for technical assistance, as well as Robert Beattie for imaging assistance. This work was supported by a European Research Council Advanced Grant 694539 to R.S.","_id":"7551","oa_version":"Published Version","status":"public","department":[{"_id":"MaJö"},{"_id":"RySh"}],"month":"01","language":[{"iso":"eng"}],"has_accepted_license":"1","abstract":[{"text":"Novelty facilitates formation of memories. The detection of novelty and storage of contextual memories are both mediated by the hippocampus, yet the mechanisms that link these two functions remain to be defined. Dentate granule cells (GCs) of the dorsal hippocampus fire upon novelty exposure forming engrams of contextual memory. However, their key excitatory inputs from the entorhinal cortex are not responsive to novelty and are insufficient to make dorsal GCs fire reliably. Here we uncover a powerful glutamatergic pathway to dorsal GCs from ventral hippocampal mossy cells (MCs) that relays novelty, and is necessary and sufficient for driving dorsal GCs activation. Furthermore, manipulation of ventral MCs activity bidirectionally regulates novelty-induced contextual memory acquisition. Our results show that ventral MCs activity controls memory formation through an intra-hippocampal interaction mechanism gated by novelty.","lang":"eng"}],"fulldoi":"https://doi.org/10.1016/j.cub.2020.09.074","date_updated":"2025-06-12T06:54:22Z","day":"11","date_created":"2020-02-28T10:56:18Z","volume":31,"article_processing_charge":"No","tmp":{"name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","image":"/images/cc_by_nc_nd.png","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","short":"CC BY-NC-ND (4.0)"},"type":"journal_article","intvolume":"        31","publisher":"Elsevier","issue":"1","file":[{"checksum":"b7b9c8bc84a08befce365c675229a7d1","file_id":"8678","success":1,"creator":"dernst","access_level":"open_access","file_name":"2021_CurrentBiology_Fredes.pdf","date_updated":"2020-10-19T13:31:28Z","date_created":"2020-10-19T13:31:28Z","content_type":"application/pdf","relation":"main_file","file_size":4915964}],"pmid":1,"article_type":"original","isi":1,"oa":1,"project":[{"name":"In situ analysis of single channel subunit composition in neurons: physiological implication in synaptic plasticity and behaviour","grant_number":"694539","_id":"25CA28EA-B435-11E9-9278-68D0E5697425","call_identifier":"H2020"}],"related_material":{"link":[{"description":"News on IST Homepage","url":"https://ist.ac.at/en/news/remembering-novelty/","relation":"press_release"}]},"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publication_status":"published","citation":{"ama":"Fredes Tolorza FA, Silva Sifuentes MA, Koppensteiner P, Kobayashi K, Jösch MA, Shigemoto R. Ventro-dorsal hippocampal pathway gates novelty-induced contextual memory formation. <i>Current Biology</i>. 2021;31(1):P25-38.E5. doi:<a href=\"https://doi.org/10.1016/j.cub.2020.09.074\">10.1016/j.cub.2020.09.074</a>","short":"F.A. Fredes Tolorza, M.A. Silva Sifuentes, P. Koppensteiner, K. Kobayashi, M.A. Jösch, R. Shigemoto, Current Biology 31 (2021) P25–38.E5.","mla":"Fredes Tolorza, Felipe A., et al. “Ventro-Dorsal Hippocampal Pathway Gates Novelty-Induced Contextual Memory Formation.” <i>Current Biology</i>, vol. 31, no. 1, Elsevier, 2021, p. P25–38.E5, doi:<a href=\"https://doi.org/10.1016/j.cub.2020.09.074\">10.1016/j.cub.2020.09.074</a>.","chicago":"Fredes Tolorza, Felipe A, Maria A Silva Sifuentes, Peter Koppensteiner, Kenta Kobayashi, Maximilian A Jösch, and Ryuichi Shigemoto. “Ventro-Dorsal Hippocampal Pathway Gates Novelty-Induced Contextual Memory Formation.” <i>Current Biology</i>. Elsevier, 2021. <a href=\"https://doi.org/10.1016/j.cub.2020.09.074\">https://doi.org/10.1016/j.cub.2020.09.074</a>.","apa":"Fredes Tolorza, F. A., Silva Sifuentes, M. A., Koppensteiner, P., Kobayashi, K., Jösch, M. A., &#38; Shigemoto, R. (2021). Ventro-dorsal hippocampal pathway gates novelty-induced contextual memory formation. <i>Current Biology</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.cub.2020.09.074\">https://doi.org/10.1016/j.cub.2020.09.074</a>","ieee":"F. A. Fredes Tolorza, M. A. Silva Sifuentes, P. Koppensteiner, K. Kobayashi, M. A. Jösch, and R. Shigemoto, “Ventro-dorsal hippocampal pathway gates novelty-induced contextual memory formation,” <i>Current Biology</i>, vol. 31, no. 1. Elsevier, p. P25–38.E5, 2021.","ista":"Fredes Tolorza FA, Silva Sifuentes MA, Koppensteiner P, Kobayashi K, Jösch MA, Shigemoto R. 2021. Ventro-dorsal hippocampal pathway gates novelty-induced contextual memory formation. Current Biology. 31(1), P25–38.E5."},"year":"2021","doi":"10.1016/j.cub.2020.09.074","ec_funded":1,"page":"P25-38.E5","ddc":["570"],"quality_controlled":"1"},{"ddc":["570"],"quality_controlled":"1","year":"2021","doi":"10.7554/ELIFE.68274","ec_funded":1,"publication_status":"published","citation":{"ista":"Bhandari P, Vandael DH, Fernández-Fernández D, Fritzius T, Kleindienst D, Önal C, Montanaro-Punzengruber J-C, Gassmann M, Jonas PM, Kulik A, Bettler B, Shigemoto R, Koppensteiner P. 2021. GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals. eLife. 10, e68274.","ieee":"P. Bhandari <i>et al.</i>, “GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals,” <i>eLife</i>, vol. 10. eLife Sciences Publications, 2021.","apa":"Bhandari, P., Vandael, D. H., Fernández-Fernández, D., Fritzius, T., Kleindienst, D., Önal, C., … Koppensteiner, P. (2021). GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals. <i>ELife</i>. eLife Sciences Publications. <a href=\"https://doi.org/10.7554/ELIFE.68274\">https://doi.org/10.7554/ELIFE.68274</a>","chicago":"Bhandari, Pradeep, David H Vandael, Diego Fernández-Fernández, Thorsten Fritzius, David Kleindienst, Cihan Önal, Jacqueline-Claire Montanaro-Punzengruber, et al. “GABAB Receptor Auxiliary Subunits Modulate Cav2.3-Mediated Release from Medial Habenula Terminals.” <i>ELife</i>. eLife Sciences Publications, 2021. <a href=\"https://doi.org/10.7554/ELIFE.68274\">https://doi.org/10.7554/ELIFE.68274</a>.","mla":"Bhandari, Pradeep, et al. “GABAB Receptor Auxiliary Subunits Modulate Cav2.3-Mediated Release from Medial Habenula Terminals.” <i>ELife</i>, vol. 10, e68274, eLife Sciences Publications, 2021, doi:<a href=\"https://doi.org/10.7554/ELIFE.68274\">10.7554/ELIFE.68274</a>.","short":"P. Bhandari, D.H. Vandael, D. Fernández-Fernández, T. Fritzius, D. Kleindienst, C. Önal, J.-C. Montanaro-Punzengruber, M. Gassmann, P.M. Jonas, A. Kulik, B. Bettler, R. Shigemoto, P. Koppensteiner, ELife 10 (2021).","ama":"Bhandari P, Vandael DH, Fernández-Fernández D, et al. GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals. <i>eLife</i>. 2021;10. doi:<a href=\"https://doi.org/10.7554/ELIFE.68274\">10.7554/ELIFE.68274</a>"},"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","isi":1,"project":[{"call_identifier":"H2020","_id":"25CA28EA-B435-11E9-9278-68D0E5697425","grant_number":"694539","name":"In situ analysis of single channel subunit composition in neurons: physiological implication in synaptic plasticity and behaviour"},{"call_identifier":"H2020","grant_number":"692692","_id":"25B7EB9E-B435-11E9-9278-68D0E5697425","name":"Biophysics and circuit function of a giant cortical glutamatergic synapse"},{"_id":"2564DBCA-B435-11E9-9278-68D0E5697425","grant_number":"665385","name":"International IST Doctoral Program","call_identifier":"H2020"}],"related_material":{"link":[{"url":"https://doi.org/10.1101/2020.04.16.045112","relation":"earlier_version"}],"record":[{"id":"19271","relation":"dissertation_contains","status":"public"},{"id":"9562","relation":"dissertation_contains","status":"public"}]},"oa":1,"pmid":1,"article_type":"original","article_number":"e68274","file":[{"date_updated":"2021-05-31T09:43:09Z","file_name":"2021_eLife_Bhandari.pdf","creator":"cziletti","access_level":"open_access","success":1,"file_id":"9440","checksum":"6ebcb79999f889766f7cd79ee134ad28","file_size":8174719,"relation":"main_file","content_type":"application/pdf","date_created":"2021-05-31T09:43:09Z"}],"intvolume":"        10","publisher":"eLife Sciences Publications","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"type":"journal_article","article_processing_charge":"No","date_created":"2021-05-30T22:01:23Z","volume":10,"abstract":[{"text":"The synaptic connection from medial habenula (MHb) to interpeduncular nucleus (IPN) is critical for emotion-related behaviors and uniquely expresses R-type Ca2+ channels (Cav2.3) and auxiliary GABAB receptor (GBR) subunits, the K+-channel tetramerization domain-containing proteins (KCTDs). Activation of GBRs facilitates or inhibits transmitter release from MHb terminals depending on the IPN subnucleus, but the role of KCTDs is unknown. We therefore examined the localization and function of Cav2.3, GBRs, and KCTDs in this pathway in mice. We show in heterologous cells that KCTD8 and KCTD12b directly bind to Cav2.3 and that KCTD8 potentiates Cav2.3 currents in the absence of GBRs. In the rostral IPN, KCTD8, KCTD12b, and Cav2.3 co-localize at the presynaptic active zone. Genetic deletion indicated a bidirectional modulation of Cav2.3-mediated release by these KCTDs with a compensatory increase of KCTD8 in the active zone in KCTD12b-deficient mice. The interaction of Cav2.3 with KCTDs therefore scales synaptic strength independent of GBR activation.","lang":"eng"}],"fulldoi":"https://doi.org/10.7554/ELIFE.68274","date_updated":"2026-10-13T22:31:06Z","day":"29","status":"public","department":[{"_id":"RySh"},{"_id":"PeJo"}],"language":[{"iso":"eng"}],"month":"04","has_accepted_license":"1","acknowledgement":"We are grateful to Akari Hagiwara and Toshihisa Ohtsuka for CAST antibody, and Masahiko Watanabe for neurexin antibody. We thank David Adams for kindly providing the stable Cav2.3 cell line. Cav2.3 KO mice were kindly provided by Tsutomu Tanabe. This project has received funding from the European Research Council (ERC) and European Commission (EC), under the European Union’s Horizon 2020 research and innovation programme (ERC grant agreement no. 694539 to Ryuichi Shigemoto, no. 692692 to Peter Jonas, and the Marie Skłodowska-Curie grant agreement no. 665385 to Cihan Önal), the Swiss National Science Foundation Grant 31003A-172881 to Bernhard Bettler and Deutsche Forschungsgemeinschaft (For 2143) and BIOSS-2 to Akos Kulik.","_id":"9437","oa_version":"Published Version","external_id":{"isi":["000651761700001"],"pmid":["33913808"]},"author":[{"orcid":"0000-0003-0863-4481","last_name":"Bhandari","full_name":"Bhandari, Pradeep","id":"45EDD1BC-F248-11E8-B48F-1D18A9856A87","first_name":"Pradeep"},{"last_name":"Vandael","id":"3AE48E0A-F248-11E8-B48F-1D18A9856A87","first_name":"David H","full_name":"Vandael, David H","orcid":"0000-0001-7577-1676"},{"last_name":"Fernández-Fernández","first_name":"Diego","full_name":"Fernández-Fernández, Diego"},{"full_name":"Fritzius, Thorsten","first_name":"Thorsten","last_name":"Fritzius"},{"full_name":"Kleindienst, David","id":"42E121A4-F248-11E8-B48F-1D18A9856A87","first_name":"David","last_name":"Kleindienst"},{"first_name":"Hüseyin C","id":"4659D740-F248-11E8-B48F-1D18A9856A87","last_name":"Önal","full_name":"Önal, Hüseyin C","orcid":"0000-0002-2771-2011"},{"id":"3786AB44-F248-11E8-B48F-1D18A9856A87","first_name":"Jacqueline-Claire","last_name":"Montanaro-Punzengruber","full_name":"Montanaro-Punzengruber, Jacqueline-Claire"},{"last_name":"Gassmann","full_name":"Gassmann, Martin","first_name":"Martin"},{"orcid":"0000-0001-5001-4804","full_name":"Jonas, Peter M","last_name":"Jonas","first_name":"Peter M","id":"353C1B58-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Akos","full_name":"Kulik, Akos","last_name":"Kulik"},{"last_name":"Bettler","full_name":"Bettler, Bernhard","first_name":"Bernhard"},{"orcid":"0000-0001-8761-9444","full_name":"Shigemoto, Ryuichi","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","last_name":"Shigemoto","first_name":"Ryuichi"},{"last_name":"Koppensteiner","full_name":"Koppensteiner, Peter","id":"3B8B25A8-F248-11E8-B48F-1D18A9856A87","first_name":"Peter","orcid":"0000-0002-3509-1948"}],"scopus_import":"1","publication":"eLife","file_date_updated":"2021-05-31T09:43:09Z","date_published":"2021-04-29T00:00:00Z","title":"GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals","publication_identifier":{"eissn":["2050-084X"]}},{"date_created":"2021-06-17T14:10:47Z","type":"dissertation","article_processing_charge":"No","has_accepted_license":"1","month":"06","acknowledged_ssus":[{"_id":"EM-Fac"}],"language":[{"iso":"eng"}],"status":"public","department":[{"_id":"GradSch"},{"_id":"RySh"}],"date_updated":"2026-07-06T13:11:44Z","day":"01","fulldoi":"https://doi.org/10.15479/at:ista:9562","abstract":[{"text":"Left-right asymmetries can be considered a fundamental organizational principle of the vertebrate central nervous system. The hippocampal CA3-CA1 pyramidal cell synaptic connection shows an input-side dependent asymmetry where the hemispheric location of the presynaptic CA3 neuron determines the synaptic properties. Left-input synapses terminating on apical dendrites in stratum radiatum have a higher density of NMDA receptor subunit GluN2B, a lower density of AMPA receptor subunit GluA1 and smaller areas with less often perforated PSDs. On the other hand, left-input synapses terminating on basal dendrites in stratum oriens have lower GluN2B densities than right-input ones. Apical and basal synapses further employ different signaling pathways involved in LTP. SDS-digested freeze-fracture replica labeling can visualize synaptic membrane proteins with high sensitivity and resolution, and has been used to reveal the asymmetry at the electron microscopic level. However, it requires time-consuming manual demarcation of the synaptic surface for quantitative measurements. To facilitate the analysis of replica labeling, I first developed a software named Darea, which utilizes deep-learning to automatize this demarcation. With Darea I characterized the synaptic distribution of NMDA and AMPA receptors as well as the voltage-gated Ca2+ channels in CA1 stratum radiatum and oriens. Second, I explored the role of GluN2B and its carboxy-terminus in the establishment of input-side dependent hippocampal asymmetry. In conditional knock-out mice lacking GluN2B expression in CA1 and GluN2B-2A swap mice, where GluN2B carboxy-terminus was exchanged to that of GluN2A, no significant asymmetries of GluN2B, GluA1 and PSD area were detected. We further discovered a previously unknown functional asymmetry of GluN2A, which was also lost in the swap mouse. These results demonstrate that GluN2B carboxy-terminus plays a critical role in normal formation of input-side dependent asymmetry.","lang":"eng"}],"author":[{"id":"42E121A4-F248-11E8-B48F-1D18A9856A87","last_name":"Kleindienst","full_name":"Kleindienst, David","first_name":"David"}],"oa_version":"Published Version","_id":"9562","publication_identifier":{"issn":["2663-337X"]},"title":"2B or not 2B: Hippocampal asymmetries mediated by NMDA receptor subunit GluN2B C-terminus and high-throughput image analysis by Deep-Learning","date_published":"2021-06-01T00:00:00Z","file_date_updated":"2022-07-02T22:30:04Z","page":"124","doi":"10.15479/at:ista:9562","year":"2021","ddc":["570"],"degree_awarded":"PhD","user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","corr_author":"1","citation":{"short":"D. Kleindienst, 2B or Not 2B: Hippocampal Asymmetries Mediated by NMDA Receptor Subunit GluN2B C-Terminus and High-Throughput Image Analysis by Deep-Learning, Institute of Science and Technology Austria, 2021.","ama":"Kleindienst D. 2B or not 2B: Hippocampal asymmetries mediated by NMDA receptor subunit GluN2B C-terminus and high-throughput image analysis by Deep-Learning. 2021. doi:<a href=\"https://doi.org/10.15479/at:ista:9562\">10.15479/at:ista:9562</a>","apa":"Kleindienst, D. (2021). <i>2B or not 2B: Hippocampal asymmetries mediated by NMDA receptor subunit GluN2B C-terminus and high-throughput image analysis by Deep-Learning</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/at:ista:9562\">https://doi.org/10.15479/at:ista:9562</a>","ieee":"D. Kleindienst, “2B or not 2B: Hippocampal asymmetries mediated by NMDA receptor subunit GluN2B C-terminus and high-throughput image analysis by Deep-Learning,” Institute of Science and Technology Austria, 2021.","ista":"Kleindienst D. 2021. 2B or not 2B: Hippocampal asymmetries mediated by NMDA receptor subunit GluN2B C-terminus and high-throughput image analysis by Deep-Learning. Institute of Science and Technology Austria.","mla":"Kleindienst, David. <i>2B or Not 2B: Hippocampal Asymmetries Mediated by NMDA Receptor Subunit GluN2B C-Terminus and High-Throughput Image Analysis by Deep-Learning</i>. Institute of Science and Technology Austria, 2021, doi:<a href=\"https://doi.org/10.15479/at:ista:9562\">10.15479/at:ista:9562</a>.","chicago":"Kleindienst, David. “2B or Not 2B: Hippocampal Asymmetries Mediated by NMDA Receptor Subunit GluN2B C-Terminus and High-Throughput Image Analysis by Deep-Learning.” Institute of Science and Technology Austria, 2021. <a href=\"https://doi.org/10.15479/at:ista:9562\">https://doi.org/10.15479/at:ista:9562</a>."},"publication_status":"published","oa":1,"related_material":{"record":[{"status":"public","relation":"part_of_dissertation","id":"9437"},{"status":"public","id":"612","relation":"part_of_dissertation"},{"id":"8532","relation":"part_of_dissertation","status":"public"},{"status":"public","relation":"part_of_dissertation","id":"9756"}]},"supervisor":[{"orcid":"0000-0001-8761-9444","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","full_name":"Shigemoto, Ryuichi","last_name":"Shigemoto","first_name":"Ryuichi"}],"OA_place":"publisher","publisher":"Institute of Science and Technology Austria","file":[{"file_name":"Thesis.pdf","date_updated":"2022-07-02T22:30:04Z","file_id":"9563","checksum":"659df5518db495f679cb1df9e9bd1d94","access_level":"open_access","creator":"dkleindienst","content_type":"application/pdf","embargo":"2022-07-01","relation":"main_file","file_size":77299142,"date_created":"2021-06-17T14:03:14Z"},{"creator":"dkleindienst","access_level":"closed","checksum":"3bcf63a2b19e5b6663be051bea332748","file_id":"9564","date_updated":"2022-07-02T22:30:04Z","file_name":"Thesis_source.zip","date_created":"2021-06-17T14:04:30Z","embargo_to":"open_access","relation":"source_file","file_size":369804895,"content_type":"application/zip"}],"alternative_title":["ISTA Thesis"]},{"doi":"10.1007/978-1-0716-1522-5_19","year":"2021","ec_funded":1,"page":"267-283","ddc":["573"],"quality_controlled":"1","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publication_status":"published","citation":{"short":"W. Kaufmann, D. Kleindienst, H. Harada, R. Shigemoto, in:, Receptor and Ion Channel Detection in the Brain, Humana Press, New York, 2021, pp. 267–283.","ama":"Kaufmann W, Kleindienst D, Harada H, Shigemoto R. High-Resolution localization and quantitation of membrane proteins by SDS-digested freeze-fracture replica labeling (SDS-FRL). In: <i>Receptor and Ion Channel Detection in the Brain</i>. Vol 169. Neuromethods. New York: Humana Press; 2021:267-283. doi:<a href=\"https://doi.org/10.1007/978-1-0716-1522-5_19\">10.1007/978-1-0716-1522-5_19</a>","ieee":"W. Kaufmann, D. Kleindienst, H. Harada, and R. Shigemoto, “High-Resolution localization and quantitation of membrane proteins by SDS-digested freeze-fracture replica labeling (SDS-FRL),” in <i>Receptor and Ion Channel Detection in the Brain</i>, vol. 169, New York: Humana Press, 2021, pp. 267–283.","apa":"Kaufmann, W., Kleindienst, D., Harada, H., &#38; Shigemoto, R. (2021). High-Resolution localization and quantitation of membrane proteins by SDS-digested freeze-fracture replica labeling (SDS-FRL). In <i>Receptor and Ion Channel Detection in the Brain</i> (Vol. 169, pp. 267–283). New York: Humana Press. <a href=\"https://doi.org/10.1007/978-1-0716-1522-5_19\">https://doi.org/10.1007/978-1-0716-1522-5_19</a>","ista":"Kaufmann W, Kleindienst D, Harada H, Shigemoto R. 2021.High-Resolution localization and quantitation of membrane proteins by SDS-digested freeze-fracture replica labeling (SDS-FRL). In: Receptor and Ion Channel Detection in the Brain. Neuromethods, vol. 169, 267–283.","mla":"Kaufmann, Walter, et al. “High-Resolution Localization and Quantitation of Membrane Proteins by SDS-Digested Freeze-Fracture Replica Labeling (SDS-FRL).” <i>Receptor and Ion Channel Detection in the Brain</i>, vol. 169, Humana Press, 2021, pp. 267–83, doi:<a href=\"https://doi.org/10.1007/978-1-0716-1522-5_19\">10.1007/978-1-0716-1522-5_19</a>.","chicago":"Kaufmann, Walter, David Kleindienst, Harumi Harada, and Ryuichi Shigemoto. “High-Resolution Localization and Quantitation of Membrane Proteins by SDS-Digested Freeze-Fracture Replica Labeling (SDS-FRL).” In <i>Receptor and Ion Channel Detection in the Brain</i>, 169:267–83. Neuromethods. New York: Humana Press, 2021. <a href=\"https://doi.org/10.1007/978-1-0716-1522-5_19\">https://doi.org/10.1007/978-1-0716-1522-5_19</a>."},"corr_author":"1","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"},{"call_identifier":"H2020","_id":"25CBA828-B435-11E9-9278-68D0E5697425","grant_number":"720270","name":"Human Brain Project Specific Grant Agreement 1"}],"das_tickbox":"1","related_material":{"record":[{"id":"9562","relation":"dissertation_contains","status":"public"}]},"intvolume":"       169","publisher":"Humana Press","keyword":["Freeze-fracture replica: Deep learning","Immunogold labeling","Integral membrane protein","Electron microscopy"],"alternative_title":["Neuromethods"],"volume":169,"date_created":"2021-07-30T09:34:56Z","type":"book_chapter","article_processing_charge":"No","series_title":"Neuromethods","status":"public","department":[{"_id":"RySh"},{"_id":"EM-Fac"}],"language":[{"iso":"eng"}],"month":"07","has_accepted_license":"1","abstract":[{"lang":"eng","text":"High-resolution visualization and quantification of membrane proteins contribute to the understanding of their functions and the roles they play in physiological and pathological conditions. Sodium dodecyl sulfate-digested freeze-fracture replica labeling (SDS-FRL) is a powerful electron microscopy method to study quantitatively the two-dimensional distribution of transmembrane proteins and their tightly associated proteins. During treatment with SDS, intracellular organelles and proteins not anchored to the replica are dissolved, whereas integral membrane proteins captured and stabilized by carbon/platinum deposition remain on the replica. Their intra- and extracellular domains become exposed on the surface of the replica, facilitating the accessibility of antibodies and, therefore, providing higher labeling efficiency than those obtained with other immunoelectron microscopy techniques. In this chapter, we describe the protocols of SDS-FRL adapted for mammalian brain samples, and optimization of the SDS treatment to increase the labeling efficiency for quantification of Cav2.1, the alpha subunit of P/Q-type voltage-dependent calcium channels utilizing deep learning algorithms."}],"fulldoi":"https://doi.org/10.1007/978-1-0716-1522-5_19","date_updated":"2026-10-13T22:31:06Z","day":"27","place":"New York","publication":"Receptor and Ion Channel Detection in the Brain","scopus_import":"1","author":[{"orcid":"0000-0001-9735-5315","id":"3F99E422-F248-11E8-B48F-1D18A9856A87","last_name":"Kaufmann","first_name":"Walter","full_name":"Kaufmann, Walter"},{"full_name":"Kleindienst, David","first_name":"David","last_name":"Kleindienst","id":"42E121A4-F248-11E8-B48F-1D18A9856A87"},{"id":"2E55CDF2-F248-11E8-B48F-1D18A9856A87","last_name":"Harada","first_name":"Harumi","full_name":"Harada, Harumi","orcid":"0000-0001-7429-7896"},{"first_name":"Ryuichi","full_name":"Shigemoto, Ryuichi","last_name":"Shigemoto","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-8761-9444"}],"acknowledgement":"This work was supported by the European Union (European Research Council Advanced grant no. 694539 and Human Brain Project Ref. 720270 to R. S.) and the Austrian Academy of Sciences (DOC fellowship to D.K.).","_id":"9756","oa_version":"None","title":"High-Resolution localization and quantitation of membrane proteins by SDS-digested freeze-fracture replica labeling (SDS-FRL)","publication_identifier":{"eisbn":["9781071615225"],"isbn":["9781071615218"]},"date_published":"2021-07-27T00:00:00Z"},{"oa":1,"isi":1,"article_type":"original","article_number":"2459","pmid":1,"file":[{"date_created":"2020-04-20T11:43:18Z","content_type":"application/pdf","file_size":2941197,"relation":"main_file","checksum":"b9d2f1657d8c4a74b01a62b474d009b0","file_id":"7669","creator":"dernst","access_level":"open_access","file_name":"2020_JournMolecSciences_Martin_Belmonte.pdf","date_updated":"2020-07-14T12:48:01Z"}],"intvolume":"        21","issue":"7","publisher":"MDPI","ddc":["570"],"quality_controlled":"1","year":"2020","doi":"10.3390/ijms21072459","publication_status":"published","citation":{"ista":"Martín-Belmonte A, Aguado C, Alfaro-Ruíz R, Moreno-Martínez AE, De La Ossa L, Martínez-Hernández J, Buisson A, Shigemoto R, Fukazawa Y, Luján R. 2020. Density of GABAB receptors is reduced in granule cells of the hippocampus in a mouse model of Alzheimer’s disease. International journal of molecular sciences. 21(7), 2459.","ieee":"A. Martín-Belmonte <i>et al.</i>, “Density of GABAB receptors is reduced in granule cells of the hippocampus in a mouse model of Alzheimer’s disease,” <i>International journal of molecular sciences</i>, vol. 21, no. 7. MDPI, 2020.","apa":"Martín-Belmonte, A., Aguado, C., Alfaro-Ruíz, R., Moreno-Martínez, A. E., De La Ossa, L., Martínez-Hernández, J., … Luján, R. (2020). Density of GABAB receptors is reduced in granule cells of the hippocampus in a mouse model of Alzheimer’s disease. <i>International Journal of Molecular Sciences</i>. MDPI. <a href=\"https://doi.org/10.3390/ijms21072459\">https://doi.org/10.3390/ijms21072459</a>","chicago":"Martín-Belmonte, Alejandro, Carolina Aguado, Rocío Alfaro-Ruíz, Ana Esther Moreno-Martínez, Luis De La Ossa, José Martínez-Hernández, Alain Buisson, Ryuichi Shigemoto, Yugo Fukazawa, and Rafael Luján. “Density of GABAB Receptors Is Reduced in Granule Cells of the Hippocampus in a Mouse Model of Alzheimer’s Disease.” <i>International Journal of Molecular Sciences</i>. MDPI, 2020. <a href=\"https://doi.org/10.3390/ijms21072459\">https://doi.org/10.3390/ijms21072459</a>.","mla":"Martín-Belmonte, Alejandro, et al. “Density of GABAB Receptors Is Reduced in Granule Cells of the Hippocampus in a Mouse Model of Alzheimer’s Disease.” <i>International Journal of Molecular Sciences</i>, vol. 21, no. 7, 2459, MDPI, 2020, doi:<a href=\"https://doi.org/10.3390/ijms21072459\">10.3390/ijms21072459</a>.","ama":"Martín-Belmonte A, Aguado C, Alfaro-Ruíz R, et al. Density of GABAB receptors is reduced in granule cells of the hippocampus in a mouse model of Alzheimer’s disease. <i>International journal of molecular sciences</i>. 2020;21(7). doi:<a href=\"https://doi.org/10.3390/ijms21072459\">10.3390/ijms21072459</a>","short":"A. Martín-Belmonte, C. Aguado, R. Alfaro-Ruíz, A.E. Moreno-Martínez, L. De La Ossa, J. Martínez-Hernández, A. Buisson, R. Shigemoto, Y. Fukazawa, R. Luján, International Journal of Molecular Sciences 21 (2020)."},"user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","oa_version":"Published Version","_id":"7664","external_id":{"isi":["000535574200201"],"pmid":["32252271"]},"publication":"International journal of molecular sciences","author":[{"last_name":"Martín-Belmonte","full_name":"Martín-Belmonte, Alejandro","first_name":"Alejandro"},{"last_name":"Aguado","full_name":"Aguado, Carolina","first_name":"Carolina"},{"last_name":"Alfaro-Ruíz","full_name":"Alfaro-Ruíz, Rocío","first_name":"Rocío"},{"first_name":"Ana Esther","full_name":"Moreno-Martínez, Ana Esther","last_name":"Moreno-Martínez"},{"full_name":"De La Ossa, Luis","last_name":"De La Ossa","first_name":"Luis"},{"full_name":"Martínez-Hernández, José","last_name":"Martínez-Hernández","first_name":"José"},{"first_name":"Alain","last_name":"Buisson","full_name":"Buisson, Alain"},{"full_name":"Shigemoto, Ryuichi","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","last_name":"Shigemoto","first_name":"Ryuichi","orcid":"0000-0001-8761-9444"},{"full_name":"Fukazawa, Yugo","first_name":"Yugo","last_name":"Fukazawa"},{"last_name":"Luján","first_name":"Rafael","full_name":"Luján, Rafael"}],"scopus_import":"1","file_date_updated":"2020-07-14T12:48:01Z","date_published":"2020-04-02T00:00:00Z","title":"Density of GABAB receptors is reduced in granule cells of the hippocampus in a mouse model of Alzheimer's disease","publication_identifier":{"eissn":["1422-0067"]},"article_processing_charge":"No","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"type":"journal_article","volume":21,"date_created":"2020-04-19T22:00:55Z","date_updated":"2026-04-02T14:27:06Z","day":"02","abstract":[{"lang":"eng","text":"Metabotropic γ-aminobutyric acid (GABAB) receptors contribute to the control of network activity and information processing in hippocampal circuits by regulating neuronal excitability and synaptic transmission. The dysfunction in the dentate gyrus (DG) has been implicated in Alzheimer´s disease (AD). Given the involvement of GABAB receptors in AD, to determine their subcellular localisation and possible alteration in granule cells of the DG in a mouse model of AD at 12 months of age, we used high-resolution immunoelectron microscopic analysis. Immunohistochemistry at the light microscopic level showed that the regional and cellular expression pattern of GABAB1 was similar in an AD model mouse expressing mutated human amyloid precursor protein and presenilin1 (APP/PS1) and in age-matched wild type mice. High-resolution immunoelectron microscopy revealed a distance-dependent gradient of immunolabelling for GABAB receptors, increasing from proximal to distal dendrites in both wild type and APP/PS1 mice. However, the overall density of GABAB receptors at the neuronal surface of these postsynaptic compartments of granule cells was significantly reduced in APP/PS1 mice. Parallel to this reduction in surface receptors, we found a significant increase in GABAB1 at cytoplasmic sites. GABAB receptors were also detected at presynaptic sites in the molecular layer of the DG. We also found a decrease in plasma membrane GABAB receptors in axon terminals contacting dendritic spines of granule cells, which was more pronounced in the outer than in the inner molecular layer. Altogether, our data showing post- and presynaptic reduction in surface GABAB receptors in the DG suggest the alteration of the GABAB-mediated modulation of excitability and synaptic transmission in granule cells, which may contribute to the cognitive dysfunctions in the APP/PS1 model of AD"}],"fulldoi":"https://doi.org/10.3390/ijms21072459","language":[{"iso":"eng"}],"month":"04","has_accepted_license":"1","status":"public","department":[{"_id":"RySh"}]},{"has_accepted_license":"1","language":[{"iso":"eng"}],"month":"03","department":[{"_id":"JoDa"},{"_id":"RySh"}],"status":"public","date_updated":"2025-06-12T07:16:39Z","day":"19","fulldoi":"https://doi.org/10.3389/fncel.2020.00063","abstract":[{"lang":"eng","text":"Acute brain slice preparation is a powerful experimental model for investigating the characteristics of synaptic function in the brain. Although brain tissue is usually cut at ice-cold temperature (CT) to facilitate slicing and avoid neuronal damage, exposure to CT causes molecular and architectural changes of synapses. To address these issues, we investigated ultrastructural and electrophysiological features of synapses in mouse acute cerebellar slices prepared at ice-cold and physiological temperature (PT). In the slices prepared at CT, we found significant spine loss and reconstruction, synaptic vesicle rearrangement and decrease in synaptic proteins, all of which were not detected in slices prepared at PT. Consistent with these structural findings, slices prepared at PT showed higher release probability. Furthermore, preparation at PT allows electrophysiological recording immediately after slicing resulting in higher detectability of long-term depression (LTD) after motor learning compared with that at CT. These results indicate substantial advantages of the slice preparation at PT for investigating synaptic functions in different physiological conditions."}],"date_created":"2020-04-19T22:00:55Z","volume":14,"tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"type":"journal_article","article_processing_charge":"Yes (via OA deal)","publication_identifier":{"issn":["1662-5102"]},"title":"Advantages of acute brain slices prepared at physiological temperature in the characterization of synaptic functions","date_published":"2020-03-19T00:00:00Z","file_date_updated":"2020-07-14T12:48:01Z","author":[{"last_name":"Eguchi","first_name":"Kohgaku","id":"2B7846DC-F248-11E8-B48F-1D18A9856A87","full_name":"Eguchi, Kohgaku","orcid":"0000-0002-6170-2546"},{"first_name":"Philipp","last_name":"Velicky","full_name":"Velicky, Philipp","id":"39BDC62C-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-2340-7431"},{"id":"3C054040-F248-11E8-B48F-1D18A9856A87","last_name":"Hollergschwandtner","full_name":"Hollergschwandtner, Elena","first_name":"Elena"},{"full_name":"Itakura, Makoto","first_name":"Makoto","last_name":"Itakura"},{"full_name":"Fukazawa, Yugo","first_name":"Yugo","last_name":"Fukazawa"},{"full_name":"Danzl, Johann G","id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","first_name":"Johann G","last_name":"Danzl","orcid":"0000-0001-8559-3973"},{"orcid":"0000-0001-8761-9444","first_name":"Ryuichi","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","full_name":"Shigemoto, Ryuichi","last_name":"Shigemoto"}],"publication":"Frontiers in Cellular Neuroscience","scopus_import":"1","external_id":{"isi":["000525582200001"],"pmid":["32265664"]},"oa_version":"Published Version","_id":"7665","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","corr_author":"1","citation":{"apa":"Eguchi, K., Velicky, P., Saeckl, E., Itakura, M., Fukazawa, Y., Danzl, J. G., &#38; Shigemoto, R. (2020). Advantages of acute brain slices prepared at physiological temperature in the characterization of synaptic functions. <i>Frontiers in Cellular Neuroscience</i>. Frontiers Media. <a href=\"https://doi.org/10.3389/fncel.2020.00063\">https://doi.org/10.3389/fncel.2020.00063</a>","ieee":"K. Eguchi <i>et al.</i>, “Advantages of acute brain slices prepared at physiological temperature in the characterization of synaptic functions,” <i>Frontiers in Cellular Neuroscience</i>, vol. 14. Frontiers Media, 2020.","ista":"Eguchi K, Velicky P, Saeckl E, Itakura M, Fukazawa Y, Danzl JG, Shigemoto R. 2020. Advantages of acute brain slices prepared at physiological temperature in the characterization of synaptic functions. Frontiers in Cellular Neuroscience. 14, 63.","mla":"Eguchi, Kohgaku, et al. “Advantages of Acute Brain Slices Prepared at Physiological Temperature in the Characterization of Synaptic Functions.” <i>Frontiers in Cellular Neuroscience</i>, vol. 14, 63, Frontiers Media, 2020, doi:<a href=\"https://doi.org/10.3389/fncel.2020.00063\">10.3389/fncel.2020.00063</a>.","chicago":"Eguchi, Kohgaku, Philipp Velicky, Elena Saeckl, Makoto Itakura, Yugo Fukazawa, Johann G Danzl, and Ryuichi Shigemoto. “Advantages of Acute Brain Slices Prepared at Physiological Temperature in the Characterization of Synaptic Functions.” <i>Frontiers in Cellular Neuroscience</i>. Frontiers Media, 2020. <a href=\"https://doi.org/10.3389/fncel.2020.00063\">https://doi.org/10.3389/fncel.2020.00063</a>.","ama":"Eguchi K, Velicky P, Saeckl E, et al. Advantages of acute brain slices prepared at physiological temperature in the characterization of synaptic functions. <i>Frontiers in Cellular Neuroscience</i>. 2020;14. doi:<a href=\"https://doi.org/10.3389/fncel.2020.00063\">10.3389/fncel.2020.00063</a>","short":"K. Eguchi, P. Velicky, E. Saeckl, M. Itakura, Y. Fukazawa, J.G. Danzl, R. Shigemoto, Frontiers in Cellular Neuroscience 14 (2020)."},"publication_status":"published","ec_funded":1,"year":"2020","doi":"10.3389/fncel.2020.00063","quality_controlled":"1","ddc":["570"],"publisher":"Frontiers Media","intvolume":"        14","file":[{"content_type":"application/pdf","file_size":9227283,"relation":"main_file","date_created":"2020-04-20T10:59:49Z","file_name":"2020_FrontiersCellularNeurosc_Eguchi.pdf","date_updated":"2020-07-14T12:48:01Z","checksum":"1c145123c6f8dc3e2e4bd5a66a1ad60e","file_id":"7668","access_level":"open_access","creator":"dernst"}],"article_number":"63","article_type":"original","pmid":1,"oa":1,"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"},{"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":"Optical control of synaptic function via adhesion molecules","_id":"265CB4D0-B435-11E9-9278-68D0E5697425","grant_number":"I03600","call_identifier":"FWF"},{"_id":"B67AFEDC-15C9-11EA-A837-991A96BB2854","name":"IST Austria Open Access Fund"}],"isi":1},{"abstract":[{"lang":"eng","text":"Type 1 metabotropic glutamate receptors (mGluR1s) are key elements in neuronal signaling. While their function is well documented in slices, requirements for their activation in vivo are poorly understood. We examine this question in adult mice in vivo using 2-photon imaging of cerebellar molecular layer interneurons (MLIs) expressing GCaMP. In anesthetized mice, parallel fiber activation evokes beam-like Cai rises in postsynaptic MLIs which depend on co-activation of mGluR1s and ionotropic glutamate receptors (iGluRs). In awake mice, blocking mGluR1 decreases Cai rises associated with locomotion. In vitro studies and freeze-fracture electron microscopy show that the iGluR-mGluR1 interaction is synergistic and favored by close association of the two classes of receptors. Altogether our results suggest that mGluR1s, acting in synergy with iGluRs, potently contribute to processing cerebellar neuronal signaling under physiological conditions."}],"fulldoi":"https://doi.org/10.7554/eLife.56839","day":"13","date_updated":"2026-04-02T14:28:17Z","department":[{"_id":"RySh"}],"status":"public","language":[{"iso":"eng"}],"month":"05","has_accepted_license":"1","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"article_processing_charge":"No","type":"journal_article","volume":9,"date_created":"2020-05-24T22:00:58Z","file_date_updated":"2020-07-14T12:48:04Z","date_published":"2020-05-13T00:00:00Z","title":"Synergism of type 1 metabotropic and ionotropic glutamate receptors in cerebellar molecular layer interneurons in vivo","publication_identifier":{"eissn":["2050-084X"]},"_id":"7878","oa_version":"Published Version","external_id":{"pmid":["32401196"],"isi":["000535191600001"]},"publication":"eLife","scopus_import":"1","author":[{"last_name":"Bao","full_name":"Bao, Jin","first_name":"Jin"},{"first_name":"Michael","full_name":"Graupner, Michael","last_name":"Graupner"},{"first_name":"Guadalupe","last_name":"Astorga","full_name":"Astorga, Guadalupe"},{"first_name":"Thibault","full_name":"Collin, Thibault","last_name":"Collin"},{"last_name":"Jalil","first_name":"Abdelali","full_name":"Jalil, Abdelali"},{"full_name":"Indriati, Dwi Wahyu","first_name":"Dwi Wahyu","last_name":"Indriati"},{"full_name":"Bradley, Jonathan","first_name":"Jonathan","last_name":"Bradley"},{"full_name":"Shigemoto, Ryuichi","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","first_name":"Ryuichi","last_name":"Shigemoto","orcid":"0000-0001-8761-9444"},{"full_name":"Llano, Isabel","last_name":"Llano","first_name":"Isabel"}],"publication_status":"published","citation":{"ista":"Bao J, Graupner M, Astorga G, Collin T, Jalil A, Indriati DW, Bradley J, Shigemoto R, Llano I. 2020. Synergism of type 1 metabotropic and ionotropic glutamate receptors in cerebellar molecular layer interneurons in vivo. eLife. 9, e56839.","ieee":"J. Bao <i>et al.</i>, “Synergism of type 1 metabotropic and ionotropic glutamate receptors in cerebellar molecular layer interneurons in vivo,” <i>eLife</i>, vol. 9. eLife Sciences Publications, 2020.","apa":"Bao, J., Graupner, M., Astorga, G., Collin, T., Jalil, A., Indriati, D. W., … Llano, I. (2020). Synergism of type 1 metabotropic and ionotropic glutamate receptors in cerebellar molecular layer interneurons in vivo. <i>ELife</i>. eLife Sciences Publications. <a href=\"https://doi.org/10.7554/eLife.56839\">https://doi.org/10.7554/eLife.56839</a>","chicago":"Bao, Jin, Michael Graupner, Guadalupe Astorga, Thibault Collin, Abdelali Jalil, Dwi Wahyu Indriati, Jonathan Bradley, Ryuichi Shigemoto, and Isabel Llano. “Synergism of Type 1 Metabotropic and Ionotropic Glutamate Receptors in Cerebellar Molecular Layer Interneurons in Vivo.” <i>ELife</i>. eLife Sciences Publications, 2020. <a href=\"https://doi.org/10.7554/eLife.56839\">https://doi.org/10.7554/eLife.56839</a>.","mla":"Bao, Jin, et al. “Synergism of Type 1 Metabotropic and Ionotropic Glutamate Receptors in Cerebellar Molecular Layer Interneurons in Vivo.” <i>ELife</i>, vol. 9, e56839, eLife Sciences Publications, 2020, doi:<a href=\"https://doi.org/10.7554/eLife.56839\">10.7554/eLife.56839</a>.","ama":"Bao J, Graupner M, Astorga G, et al. Synergism of type 1 metabotropic and ionotropic glutamate receptors in cerebellar molecular layer interneurons in vivo. <i>eLife</i>. 2020;9. doi:<a href=\"https://doi.org/10.7554/eLife.56839\">10.7554/eLife.56839</a>","short":"J. Bao, M. Graupner, G. Astorga, T. Collin, A. Jalil, D.W. Indriati, J. Bradley, R. Shigemoto, I. Llano, ELife 9 (2020)."},"user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","ddc":["570"],"quality_controlled":"1","year":"2020","doi":"10.7554/eLife.56839","file":[{"content_type":"application/pdf","relation":"main_file","file_size":4832050,"date_created":"2020-05-26T09:34:54Z","file_name":"2020_eLife_Bao.pdf","date_updated":"2020-07-14T12:48:04Z","file_id":"7891","checksum":"8ea99bb6660cc407dbdb00c173b01683","creator":"dernst","access_level":"open_access"}],"intvolume":"         9","publisher":"eLife Sciences Publications","isi":1,"oa":1,"pmid":1,"article_type":"original","article_number":"e56839"},{"pmid":1,"article_type":"original","isi":1,"oa":1,"intvolume":"        40","publisher":"Society for Neuroscience","issue":"21","file":[{"date_created":"2020-06-02T09:12:16Z","relation":"main_file","file_size":3817360,"content_type":"application/pdf","access_level":"open_access","creator":"dernst","checksum":"6571607ea9036154b67cc78e848a7f7d","file_id":"7912","date_updated":"2020-07-14T12:48:05Z","file_name":"2020_JourNeuroscience_Wang.pdf"}],"year":"2020","doi":"10.1523/JNEUROSCI.2946-19.2020","page":"4103-4115","ddc":["570"],"quality_controlled":"1","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publication_status":"published","citation":{"mla":"Wang, Han Ying, et al. “Frequency-Dependent Block of Excitatory Neurotransmission by Isoflurane via Dual Presynaptic Mechanisms.” <i>Journal of Neuroscience</i>, vol. 40, no. 21, Society for Neuroscience, 2020, pp. 4103–15, doi:<a href=\"https://doi.org/10.1523/JNEUROSCI.2946-19.2020\">10.1523/JNEUROSCI.2946-19.2020</a>.","chicago":"Wang, Han Ying, Kohgaku Eguchi, Takayuki Yamashita, and Tomoyuki Takahashi. “Frequency-Dependent Block of Excitatory Neurotransmission by Isoflurane via Dual Presynaptic Mechanisms.” <i>Journal of Neuroscience</i>. Society for Neuroscience, 2020. <a href=\"https://doi.org/10.1523/JNEUROSCI.2946-19.2020\">https://doi.org/10.1523/JNEUROSCI.2946-19.2020</a>.","apa":"Wang, H. Y., Eguchi, K., Yamashita, T., &#38; Takahashi, T. (2020). Frequency-dependent block of excitatory neurotransmission by isoflurane via dual presynaptic mechanisms. <i>Journal of Neuroscience</i>. Society for Neuroscience. <a href=\"https://doi.org/10.1523/JNEUROSCI.2946-19.2020\">https://doi.org/10.1523/JNEUROSCI.2946-19.2020</a>","ieee":"H. Y. Wang, K. Eguchi, T. Yamashita, and T. Takahashi, “Frequency-dependent block of excitatory neurotransmission by isoflurane via dual presynaptic mechanisms,” <i>Journal of Neuroscience</i>, vol. 40, no. 21. Society for Neuroscience, pp. 4103–4115, 2020.","ista":"Wang HY, Eguchi K, Yamashita T, Takahashi T. 2020. Frequency-dependent block of excitatory neurotransmission by isoflurane via dual presynaptic mechanisms. Journal of Neuroscience. 40(21), 4103–4115.","ama":"Wang HY, Eguchi K, Yamashita T, Takahashi T. Frequency-dependent block of excitatory neurotransmission by isoflurane via dual presynaptic mechanisms. <i>Journal of Neuroscience</i>. 2020;40(21):4103-4115. doi:<a href=\"https://doi.org/10.1523/JNEUROSCI.2946-19.2020\">10.1523/JNEUROSCI.2946-19.2020</a>","short":"H.Y. Wang, K. Eguchi, T. Yamashita, T. Takahashi, Journal of Neuroscience 40 (2020) 4103–4115."},"external_id":{"isi":["000535694700004"],"pmid":["32327530"]},"author":[{"first_name":"Han Ying","last_name":"Wang","full_name":"Wang, Han Ying"},{"orcid":"0000-0002-6170-2546","full_name":"Eguchi, Kohgaku","id":"2B7846DC-F248-11E8-B48F-1D18A9856A87","last_name":"Eguchi","first_name":"Kohgaku"},{"first_name":"Takayuki","last_name":"Yamashita","full_name":"Yamashita, Takayuki"},{"full_name":"Takahashi, Tomoyuki","first_name":"Tomoyuki","last_name":"Takahashi"}],"scopus_import":"1","publication":"Journal of Neuroscience","_id":"7908","oa_version":"Published Version","title":"Frequency-dependent block of excitatory neurotransmission by isoflurane via dual presynaptic mechanisms","publication_identifier":{"eissn":["1529-2401"]},"file_date_updated":"2020-07-14T12:48:05Z","date_published":"2020-05-20T00:00:00Z","date_created":"2020-05-31T22:00:48Z","volume":40,"article_processing_charge":"No","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"type":"journal_article","status":"public","department":[{"_id":"RySh"}],"month":"05","language":[{"iso":"eng"}],"has_accepted_license":"1","abstract":[{"text":"Volatile anesthetics are widely used for surgery, but neuronal mechanisms of anesthesia remain unidentified. At the calyx of Held in brainstem slices from rats of either sex, isoflurane at clinical doses attenuated EPSCs by decreasing the release probability and the number of readily releasable vesicles. In presynaptic recordings of Ca2+ currents and exocytic capacitance changes, isoflurane attenuated exocytosis by inhibiting Ca2+ currents evoked by a short presynaptic depolarization, whereas it inhibited exocytosis evoked by a prolonged depolarization via directly blocking exocytic machinery downstream of Ca2+ influx. Since the length of presynaptic depolarization can simulate the frequency of synaptic inputs, isoflurane anesthesia is likely mediated by distinct dual mechanisms, depending on input frequencies. In simultaneous presynaptic and postsynaptic action potential recordings, isoflurane impaired the fidelity of repetitive spike transmission, more strongly at higher frequencies. Furthermore, in the cerebrum of adult mice, isoflurane inhibited monosynaptic corticocortical spike transmission, preferentially at a higher frequency. We conclude that dual presynaptic mechanisms operate for the anesthetic action of isoflurane, of which direct inhibition of exocytic machinery plays a low-pass filtering role in spike transmission at central excitatory synapses.","lang":"eng"}],"fulldoi":"https://doi.org/10.1523/JNEUROSCI.2946-19.2020","date_updated":"2025-03-07T08:29:32Z","day":"20"},{"publication_identifier":{"issn":["0021-9967"],"eissn":["1096-9861"]},"title":"Expression mapping, quantification, and complex formation of GluD1 and GluD2 glutamate receptors in adult mouse brain","date_published":"2020-04-01T00:00:00Z","publication":"Journal of Comparative Neurology","scopus_import":"1","author":[{"last_name":"Nakamoto","full_name":"Nakamoto, Chihiro","first_name":"Chihiro"},{"last_name":"Konno","full_name":"Konno, Kohtarou","first_name":"Kohtarou"},{"first_name":"Taisuke","last_name":"Miyazaki","full_name":"Miyazaki, Taisuke"},{"full_name":"Nakatsukasa, Ena","last_name":"Nakatsukasa","first_name":"Ena"},{"first_name":"Rie","full_name":"Natsume, Rie","last_name":"Natsume"},{"last_name":"Abe","full_name":"Abe, Manabu","first_name":"Manabu"},{"first_name":"Meiko","last_name":"Kawamura","full_name":"Kawamura, Meiko"},{"full_name":"Fukazawa, Yugo","first_name":"Yugo","last_name":"Fukazawa"},{"full_name":"Shigemoto, Ryuichi","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","first_name":"Ryuichi","last_name":"Shigemoto","orcid":"0000-0001-8761-9444"},{"last_name":"Yamasaki","first_name":"Miwako","full_name":"Yamasaki, Miwako"},{"first_name":"Kenji","last_name":"Sakimura","full_name":"Sakimura, Kenji"},{"full_name":"Watanabe, Masahiko","first_name":"Masahiko","last_name":"Watanabe"}],"external_id":{"pmid":["31625608"],"isi":["000496410200001"]},"oa_version":"None","_id":"7148","acknowledgement":"This study was supported by Grants-in-Aid for Scientific Research to K.K. (18K06813), Y.M. (17K08503, 17H0631319), and K.S. (16H04650) and a grant for Scientific Research on Innovative Areas to K.S (16H06276) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT). We thank K. Akashi, I. Watanabe-Iida, Y. Suzuki, and H. Azechi for technical assistance and advice, and H. Uchida for valuable discussions. We thank E. Kushiya,I. Yabe, C. Ohori, Y. Mochizuki, Y. Ishikawa, and N. Ishimoto for technical assistance in generating GluD1-KO mice.","has_accepted_license":"1","language":[{"iso":"eng"}],"month":"04","department":[{"_id":"RySh"}],"status":"public","date_updated":"2023-08-17T14:06:50Z","day":"01","fulldoi":"https://doi.org/10.1002/cne.24792","abstract":[{"lang":"eng","text":"In the cerebellum, GluD2 is exclusively expressed in Purkinje cells, where it regulates synapse formation and regeneration, synaptic plasticity, and motor learning. Delayed cognitive development in humans with GluD2 gene mutations suggests extracerebellar functions of GluD2. However, extracerebellar expression of GluD2 and its relationship with that of GluD1 are poorly understood. GluD2 mRNA and protein were widely detected, with relatively high levels observed in the olfactory glomerular layer, medial prefrontal cortex, cingulate cortex, retrosplenial granular cortex, olfactory tubercle, subiculum, striatum, lateral septum, anterodorsal thalamic nucleus, and arcuate hypothalamic nucleus. These regions were also enriched for GluD1, and many individual neurons coexpressed the two GluDs. In the retrosplenial granular cortex, GluD1 and GluD2 were selectively expressed at PSD‐95‐expressing glutamatergic synapses, and their coexpression on the same synapses was shown by SDS‐digested freeze‐fracture replica labeling. Biochemically, GluD1 and GluD2 formed coimmunoprecipitable complex formation in HEK293T cells and in the cerebral cortex and hippocampus. We further estimated the relative protein amount by quantitative immunoblotting using GluA2/GluD2 and GluA2/GluD1 chimeric proteins as standards for titration of GluD1 and GluD2 antibodies. Intriguingly, the relative amount of GluD2 was almost comparable to that of GluD1 in the postsynaptic density fraction prepared from the cerebral cortex and hippocampus. In contrast, GluD2 was overwhelmingly predominant in the cerebellum. Thus, we have determined the relative extracerebellar expression of GluD1 and GluD2 at regional, neuronal, and synaptic levels. These data provide a molecular–anatomical basis for possible competitive and cooperative interactions of GluD family members at synapses in various brain regions."}],"volume":528,"date_created":"2019-12-04T16:09:29Z","type":"journal_article","article_processing_charge":"No","issue":"6","publisher":"Wiley","intvolume":"       528","article_type":"original","pmid":1,"isi":1,"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","citation":{"ista":"Nakamoto C, Konno K, Miyazaki T, Nakatsukasa E, Natsume R, Abe M, Kawamura M, Fukazawa Y, Shigemoto R, Yamasaki M, Sakimura K, Watanabe M. 2020. Expression mapping, quantification, and complex formation of GluD1 and GluD2 glutamate receptors in adult mouse brain. Journal of Comparative Neurology. 528(6), 1003–1027.","ieee":"C. Nakamoto <i>et al.</i>, “Expression mapping, quantification, and complex formation of GluD1 and GluD2 glutamate receptors in adult mouse brain,” <i>Journal of Comparative Neurology</i>, vol. 528, no. 6. Wiley, pp. 1003–1027, 2020.","apa":"Nakamoto, C., Konno, K., Miyazaki, T., Nakatsukasa, E., Natsume, R., Abe, M., … Watanabe, M. (2020). Expression mapping, quantification, and complex formation of GluD1 and GluD2 glutamate receptors in adult mouse brain. <i>Journal of Comparative Neurology</i>. Wiley. <a href=\"https://doi.org/10.1002/cne.24792\">https://doi.org/10.1002/cne.24792</a>","chicago":"Nakamoto, Chihiro, Kohtarou Konno, Taisuke Miyazaki, Ena Nakatsukasa, Rie Natsume, Manabu Abe, Meiko Kawamura, et al. “Expression Mapping, Quantification, and Complex Formation of GluD1 and GluD2 Glutamate Receptors in Adult Mouse Brain.” <i>Journal of Comparative Neurology</i>. Wiley, 2020. <a href=\"https://doi.org/10.1002/cne.24792\">https://doi.org/10.1002/cne.24792</a>.","mla":"Nakamoto, Chihiro, et al. “Expression Mapping, Quantification, and Complex Formation of GluD1 and GluD2 Glutamate Receptors in Adult Mouse Brain.” <i>Journal of Comparative Neurology</i>, vol. 528, no. 6, Wiley, 2020, pp. 1003–27, doi:<a href=\"https://doi.org/10.1002/cne.24792\">10.1002/cne.24792</a>.","ama":"Nakamoto C, Konno K, Miyazaki T, et al. Expression mapping, quantification, and complex formation of GluD1 and GluD2 glutamate receptors in adult mouse brain. <i>Journal of Comparative Neurology</i>. 2020;528(6):1003-1027. doi:<a href=\"https://doi.org/10.1002/cne.24792\">10.1002/cne.24792</a>","short":"C. Nakamoto, K. Konno, T. Miyazaki, E. Nakatsukasa, R. Natsume, M. Abe, M. Kawamura, Y. Fukazawa, R. Shigemoto, M. Yamasaki, K. Sakimura, M. Watanabe, Journal of Comparative Neurology 528 (2020) 1003–1027."},"publication_status":"published","page":"1003-1027","doi":"10.1002/cne.24792","year":"2020","quality_controlled":"1","ddc":["571","599"]},{"file":[{"date_created":"2020-09-22T09:47:19Z","content_type":"application/pdf","file_size":4220935,"relation":"main_file","checksum":"549cc1b18f638a21d17a939ba5563fa9","file_id":"8554","success":1,"access_level":"open_access","creator":"dernst","file_name":"2020_BrainPathology_MartinBelmonte.pdf","date_updated":"2020-09-22T09:47:19Z"}],"issue":"3","publisher":"Wiley","intvolume":"        30","oa":1,"project":[{"name":"Human Brain Project Specific Grant Agreement 1","_id":"25CBA828-B435-11E9-9278-68D0E5697425","grant_number":"720270","call_identifier":"H2020"},{"call_identifier":"H2020","name":"Human Brain Project Specific Grant Agreement 2","_id":"26436750-B435-11E9-9278-68D0E5697425","grant_number":"785907"}],"isi":1,"article_type":"original","pmid":1,"citation":{"chicago":"Martín-Belmonte, Alejandro, Carolina Aguado, Rocío Alfaro-Ruíz, Ana Esther Moreno-Martínez, Luis De La Ossa, José Martínez-Hernández, Alain Buisson, et al. “Reduction in the Neuronal Surface of Post and Presynaptic GABA&#62;B&#60; Receptors in the Hippocampus in a Mouse Model of Alzheimer’s Disease.” <i>Brain Pathology</i>. Wiley, 2020. <a href=\"https://doi.org/10.1111/bpa.12802\">https://doi.org/10.1111/bpa.12802</a>.","mla":"Martín-Belmonte, Alejandro, et al. “Reduction in the Neuronal Surface of Post and Presynaptic GABA&#62;B&#60; Receptors in the Hippocampus in a Mouse Model of Alzheimer’s Disease.” <i>Brain Pathology</i>, vol. 30, no. 3, Wiley, 2020, pp. 554–75, doi:<a href=\"https://doi.org/10.1111/bpa.12802\">10.1111/bpa.12802</a>.","ista":"Martín-Belmonte A, Aguado C, Alfaro-Ruíz R, Moreno-Martínez AE, De La Ossa L, Martínez-Hernández J, Buisson A, Früh S, Bettler B, Shigemoto R, Fukazawa Y, Luján R. 2020. Reduction in the neuronal surface of post and presynaptic GABA&#62;B&#60; receptors in the hippocampus in a mouse model of Alzheimer’s disease. Brain Pathology. 30(3), 554–575.","apa":"Martín-Belmonte, A., Aguado, C., Alfaro-Ruíz, R., Moreno-Martínez, A. E., De La Ossa, L., Martínez-Hernández, J., … Luján, R. (2020). Reduction in the neuronal surface of post and presynaptic GABA&#62;B&#60; receptors in the hippocampus in a mouse model of Alzheimer’s disease. <i>Brain Pathology</i>. Wiley. <a href=\"https://doi.org/10.1111/bpa.12802\">https://doi.org/10.1111/bpa.12802</a>","ieee":"A. Martín-Belmonte <i>et al.</i>, “Reduction in the neuronal surface of post and presynaptic GABA&#62;B&#60; receptors in the hippocampus in a mouse model of Alzheimer’s disease,” <i>Brain Pathology</i>, vol. 30, no. 3. Wiley, pp. 554–575, 2020.","ama":"Martín-Belmonte A, Aguado C, Alfaro-Ruíz R, et al. Reduction in the neuronal surface of post and presynaptic GABA&#62;B&#60; receptors in the hippocampus in a mouse model of Alzheimer’s disease. <i>Brain Pathology</i>. 2020;30(3):554-575. doi:<a href=\"https://doi.org/10.1111/bpa.12802\">10.1111/bpa.12802</a>","short":"A. Martín-Belmonte, C. Aguado, R. Alfaro-Ruíz, A.E. Moreno-Martínez, L. De La Ossa, J. Martínez-Hernández, A. Buisson, S. Früh, B. Bettler, R. Shigemoto, Y. Fukazawa, R. Luján, Brain Pathology 30 (2020) 554–575."},"publication_status":"published","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","quality_controlled":"1","ddc":["570"],"page":"554-575","ec_funded":1,"doi":"10.1111/bpa.12802","year":"2020","date_published":"2020-05-01T00:00:00Z","file_date_updated":"2020-09-22T09:47:19Z","publication_identifier":{"eissn":["1750-3639"],"issn":["1015-6305"]},"title":"Reduction in the neuronal surface of post and presynaptic GABA>B< receptors in the hippocampus in a mouse model of Alzheimer's disease","oa_version":"Published Version","_id":"7207","scopus_import":"1","publication":"Brain Pathology","author":[{"full_name":"Martín-Belmonte, Alejandro","last_name":"Martín-Belmonte","first_name":"Alejandro"},{"full_name":"Aguado, Carolina","last_name":"Aguado","first_name":"Carolina"},{"full_name":"Alfaro-Ruíz, Rocío","last_name":"Alfaro-Ruíz","first_name":"Rocío"},{"first_name":"Ana Esther","last_name":"Moreno-Martínez","full_name":"Moreno-Martínez, Ana Esther"},{"first_name":"Luis","full_name":"De La Ossa, Luis","last_name":"De La Ossa"},{"first_name":"José","full_name":"Martínez-Hernández, José","last_name":"Martínez-Hernández"},{"first_name":"Alain","last_name":"Buisson","full_name":"Buisson, Alain"},{"first_name":"Simon","full_name":"Früh, Simon","last_name":"Früh"},{"last_name":"Bettler","first_name":"Bernhard","full_name":"Bettler, Bernhard"},{"orcid":"0000-0001-8761-9444","last_name":"Shigemoto","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","full_name":"Shigemoto, Ryuichi","first_name":"Ryuichi"},{"first_name":"Yugo","full_name":"Fukazawa, Yugo","last_name":"Fukazawa"},{"first_name":"Rafael","full_name":"Luján, Rafael","last_name":"Luján"}],"external_id":{"isi":["000502270900001"],"pmid":["31729777"]},"day":"01","date_updated":"2025-07-10T11:54:22Z","fulldoi":"https://doi.org/10.1111/bpa.12802","abstract":[{"lang":"eng","text":"The hippocampus plays key roles in learning and memory and is a main target of Alzheimer's disease (AD), which causes progressive memory impairments. Despite numerous investigations about the processes required for the normal hippocampal functions, the neurotransmitter receptors involved in the synaptic deficits by which AD disables the hippocampus are not yet characterized. By combining histoblots, western blots, immunohistochemistry and high‐resolution immunoelectron microscopic methods for GABAB receptors, this study provides a quantitative description of the expression and the subcellular localization of GABAB1 in the hippocampus in a mouse model of AD at 1, 6 and 12 months of age. Western blots and histoblots showed that the total amount of protein and the laminar expression pattern of GABAB1 were similar in APP/PS1 mice and in age‐matched wild‐type mice. In contrast, immunoelectron microscopic techniques showed that the subcellular localization of GABAB1 subunit did not change significantly in APP/PS1 mice at 1 month of age, was significantly reduced in the stratum lacunosum‐moleculare of CA1 pyramidal cells at 6 months of age and significantly reduced at the membrane surface of CA1 pyramidal cells at 12 months of age. This reduction of plasma membrane GABAB1 was paralleled by a significant increase of the subunit at the intracellular sites. We further observed a decrease of membrane‐targeted GABAB receptors in axon terminals contacting CA1 pyramidal cells. Our data demonstrate compartment‐ and age‐dependent reduction of plasma membrane‐targeted GABAB receptors in the CA1 region of the hippocampus, suggesting that this decrease might be enough to alter the GABAB‐mediated synaptic transmission taking place in AD."}],"has_accepted_license":"1","language":[{"iso":"eng"}],"month":"05","department":[{"_id":"RySh"}],"status":"public","article_processing_charge":"No","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"type":"journal_article","volume":30,"date_created":"2019-12-22T23:00:43Z"},{"has_accepted_license":"1","month":"01","language":[{"iso":"eng"}],"department":[{"_id":"RySh"}],"status":"public","date_updated":"2026-04-16T08:27:29Z","day":"02","fulldoi":"https://doi.org/10.1523/JNEUROSCI.1571-19.2019","abstract":[{"lang":"eng","text":"Cytoskeletal filaments such as microtubules (MTs) and filamentous actin (F-actin) dynamically support cell structure and functions. In central presynaptic terminals, F-actin is expressed along the release edge and reportedly plays diverse functional roles, but whether axonal MTs extend deep into terminals and play any physiological role remains controversial. At the calyx of Held in rats of either sex, confocal and high-resolution microscopy revealed that MTs enter deep into presynaptic terminal swellings and partially colocalize with a subset of synaptic vesicles (SVs). Electrophysiological analysis demonstrated that depolymerization of MTs specifically prolonged the slow-recovery time component of EPSCs from short-term depression induced by a train of high-frequency stimulation, whereas depolymerization of F-actin specifically prolonged the fast-recovery component. In simultaneous presynaptic and postsynaptic action potential recordings, depolymerization of MTs or F-actin significantly impaired the fidelity of high-frequency neurotransmission. We conclude that MTs and F-actin differentially contribute to slow and fast SV replenishment, thereby maintaining high-frequency neurotransmission."}],"date_created":"2020-01-19T23:00:38Z","volume":40,"tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"article_processing_charge":"No","type":"journal_article","publication_identifier":{"issn":["0270-6474"],"eissn":["1529-2401"]},"title":"Microtubule and actin differentially regulate synaptic vesicle cycling to maintain high-frequency neurotransmission","date_published":"2020-01-02T00:00:00Z","file_date_updated":"2020-07-14T12:47:56Z","author":[{"full_name":"Piriya Ananda Babu, Lashmi","first_name":"Lashmi","last_name":"Piriya Ananda Babu"},{"full_name":"Wang, Han Ying","first_name":"Han Ying","last_name":"Wang"},{"orcid":"0000-0002-6170-2546","id":"2B7846DC-F248-11E8-B48F-1D18A9856A87","full_name":"Eguchi, Kohgaku","first_name":"Kohgaku","last_name":"Eguchi"},{"last_name":"Guillaud","full_name":"Guillaud, Laurent","first_name":"Laurent"},{"full_name":"Takahashi, Tomoyuki","first_name":"Tomoyuki","last_name":"Takahashi"}],"publication":"Journal of neuroscience","scopus_import":"1","external_id":{"pmid":["31767677"],"isi":["000505167600013"]},"oa_version":"Published Version","_id":"7339","user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","citation":{"mla":"Piriya Ananda Babu, Lashmi, et al. “Microtubule and Actin Differentially Regulate Synaptic Vesicle Cycling to Maintain High-Frequency Neurotransmission.” <i>Journal of Neuroscience</i>, vol. 40, no. 1, Society for Neuroscience, 2020, pp. 131–42, doi:<a href=\"https://doi.org/10.1523/JNEUROSCI.1571-19.2019\">10.1523/JNEUROSCI.1571-19.2019</a>.","chicago":"Piriya Ananda Babu, Lashmi, Han Ying Wang, Kohgaku Eguchi, Laurent Guillaud, and Tomoyuki Takahashi. “Microtubule and Actin Differentially Regulate Synaptic Vesicle Cycling to Maintain High-Frequency Neurotransmission.” <i>Journal of Neuroscience</i>. Society for Neuroscience, 2020. <a href=\"https://doi.org/10.1523/JNEUROSCI.1571-19.2019\">https://doi.org/10.1523/JNEUROSCI.1571-19.2019</a>.","ieee":"L. Piriya Ananda Babu, H. Y. Wang, K. Eguchi, L. Guillaud, and T. Takahashi, “Microtubule and actin differentially regulate synaptic vesicle cycling to maintain high-frequency neurotransmission,” <i>Journal of neuroscience</i>, vol. 40, no. 1. Society for Neuroscience, pp. 131–142, 2020.","apa":"Piriya Ananda Babu, L., Wang, H. Y., Eguchi, K., Guillaud, L., &#38; Takahashi, T. (2020). Microtubule and actin differentially regulate synaptic vesicle cycling to maintain high-frequency neurotransmission. <i>Journal of Neuroscience</i>. Society for Neuroscience. <a href=\"https://doi.org/10.1523/JNEUROSCI.1571-19.2019\">https://doi.org/10.1523/JNEUROSCI.1571-19.2019</a>","ista":"Piriya Ananda Babu L, Wang HY, Eguchi K, Guillaud L, Takahashi T. 2020. Microtubule and actin differentially regulate synaptic vesicle cycling to maintain high-frequency neurotransmission. Journal of neuroscience. 40(1), 131–142.","ama":"Piriya Ananda Babu L, Wang HY, Eguchi K, Guillaud L, Takahashi T. Microtubule and actin differentially regulate synaptic vesicle cycling to maintain high-frequency neurotransmission. <i>Journal of neuroscience</i>. 2020;40(1):131-142. doi:<a href=\"https://doi.org/10.1523/JNEUROSCI.1571-19.2019\">10.1523/JNEUROSCI.1571-19.2019</a>","short":"L. Piriya Ananda Babu, H.Y. Wang, K. Eguchi, L. Guillaud, T. Takahashi, Journal of Neuroscience 40 (2020) 131–142."},"publication_status":"published","page":"131-142","doi":"10.1523/JNEUROSCI.1571-19.2019","year":"2020","quality_controlled":"1","ddc":["570"],"issue":"1","publisher":"Society for Neuroscience","intvolume":"        40","file":[{"file_size":4460781,"relation":"main_file","content_type":"application/pdf","date_created":"2020-01-20T14:44:10Z","date_updated":"2020-07-14T12:47:56Z","file_name":"2020_JourNeuroscience_Piriya.pdf","creator":"dernst","access_level":"open_access","file_id":"7345","checksum":"92f5e8a47f454fc131fb94cd7f106e60"}],"article_type":"original","pmid":1,"oa":1,"isi":1},{"abstract":[{"text":"The medial habenula (MHb) is an evolutionary conserved epithalamic structure important for the modulation of emotional memory. It is involved in regulation of anxiety, compulsive behavior, addiction (nicotinic and opioid), sexual and feeding behavior. MHb receives inputs from septal regions and projects exclusively to the interpeduncular nucleus (IPN). Distinct sub-regions of the septum project to different subnuclei of MHb: the bed nucleus of anterior commissure projects to dorsal MHb and the triangular septum projects to ventral MHb. Furthermore, the dorsal and ventral MHb project to the lateral and rostral/central IPN, respectively. Importantly, these projections have unique features of prominent co-release of different neurotransmitters and requirement of a peculiar type of calcium channel for release. In general, synaptic neurotransmission requires an activity-dependent influx of Ca2+ into the presynaptic terminal through voltage-gated calcium channels. The calcium channel family most commonly involved in neurotransmitter release comprises three members, P/Q-, N- and R-type with Cav2.1, Cav2.2 and Cav2.3 subunits, respectively. In contrast to most CNS synapses that mainly express Cav2.1 and/or Cav2.2, MHb terminals in the IPN exclusively express Cav2.3. In other parts of the brain, such as the hippocampus, Cav2.3 is mostly located to postsynaptic elements. This unusual presynaptic location of Cav2.3 in the MHb-IPN pathway implies unique mechanisms of glutamate release in this pathway. One potential example of such uniqueness is the facilitation of release by GABAB receptor (GBR) activation. Presynaptic GBRs usually inhibit the release of neurotransmitters by inhibiting presynaptic calcium channels. MHb shows the highest expression levels of GBR in the brain. GBRs comprise two subunits, GABAB1 (GB1) and GABAB2 (GB2), and are associated with auxiliary subunits, called potassium channel tetramerization domain containing proteins (KCTD) 8, 12, 12b and 16. Among these four subunits, KCTD12b is exclusively expressed in ventral MHb, and KCTD8 shows the strongest expression in the whole MHb among other brain regions, indicating that KCTD8 and KCTD12b may be involved in the unique mechanisms of neurotransmitter release mediated by Cav2.3 and regulated by GBRs in this pathway. \r\nIn the present study, we first verified that neurotransmission in both dorsal and ventral MHb-IPN pathways is mainly mediated by Cav2.3 using a selective blocker of R-type channels, SNX-482. We next found that baclofen, a GBR agonist, has facilitatory effects on release from ventral MHb terminal in rostral IPN, whereas it has inhibitory effects on release from dorsal MHb terminals in lateral IPN, indicating that KCTD12b expressed exclusively in ventral MHb may have a role in the facilitatory effects of GBR activation. In a heterologous expression system using HEK cells, we found that KCTD8 and KCTD12b but not KCTD12 directly bind with Cav2.3. Pre-embedding immunogold electron microscopy data show that Cav2.3 and KCTD12b are distributed most densely in presynaptic active zone in IPN with KCTD12b being present only in rostral/central but not lateral IPN, whereas GABAB, KCTD8 and KCTD12 are distributed most densely in perisynaptic sites with KCTD12 present more frequently in postsynaptic elements and only in rostral/central IPN. In freeze-fracture replica labelling, Cav2.3, KCTD8 and KCTD12b are co-localized with each other in the same active zone indicating that they may form complexes regulating vesicle release in rostral IPN. \r\nOn electrophysiological studies of wild type (WT) mice, we found that paired-pulse ratio in rostral IPN of KCTD12b knock-out (KO) mice is lower than those of WT and KCTD8 KO mice. Consistent with this finding, in mean variance analysis, release probability in rostral IPN of KCTD12b KO mice is higher than that of WT and KCTD8 KO mice. Although paired-pulse ratios are not different between WT and KCTD8 KO mice, the mean variance analysis revealed significantly lower release probability in rostral IPN of KCTD8 KO than WT mice. These results demonstrate bidirectional regulation of Cav2.3-mediated release by KCTD8 and KCTD12b without GBR activation in rostral IPN. Finally, we examined the baclofen effects in rostral IPN of KCTD8 and KCTD12b KO mice, and found the facilitation of release remained in both KO mice, indicating that the peculiar effects of the GBR activation in this pathway do not depend on the selective expression of these KCTD subunits in ventral MHb. However, we found that presynaptic potentiation of evoked EPSC amplitude by baclofen falls to baseline after washout faster in KCTD12b KO mice than WT, KCTD8 KO and KCTD8/12b double KO mice. This result indicates that KCTD12b is involved in sustained potentiation of vesicle release by GBR activation, whereas KCTD8 is involved in its termination in the absence of KCTD12b. Consistent with these functional findings, replica labelling revealed an increase in density of KCTD8, but not Cav2.3 or GBR at active zone in rostral IPN of KCTD12b KO mice compared with that of WT mice, suggesting that increased association of KCTD8 with Cav2.3 facilitates the release probability and termination of the GBR effect in the absence of KCTD12b.\r\nIn summary, our study provided new insights into the physiological roles of presynaptic Cav2.3, GBRs and their auxiliary subunits KCTDs at an evolutionary conserved neuronal circuit. Future studies will be required to identify the exact molecular mechanism underlying the GBR-mediated presynaptic potentiation on ventral MHb terminals. It remains to be determined whether the prominent presence of presynaptic KCTDs at active zone could exert similar neuromodulatory functions in different pathways of the brain.\r\n","lang":"eng"}],"fulldoi":"https://doi.org/10.15479/AT:ISTA:7525","date_updated":"2026-04-08T07:27:27Z","day":"28","status":"public","department":[{"_id":"RySh"}],"language":[{"iso":"eng"}],"acknowledged_ssus":[{"_id":"EM-Fac"}],"month":"02","has_accepted_license":"1","article_processing_charge":"No","type":"dissertation","date_created":"2020-02-26T10:56:37Z","file_date_updated":"2021-03-01T23:30:04Z","date_published":"2020-02-28T00:00:00Z","title":"Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway","publication_identifier":{"issn":["2663-337X"]},"_id":"7525","oa_version":"Published Version","author":[{"first_name":"Pradeep","last_name":"Bhandari","full_name":"Bhandari, Pradeep","id":"45EDD1BC-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-0863-4481"}],"publication_status":"published","citation":{"ama":"Bhandari P. Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway. 2020. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:7525\">10.15479/AT:ISTA:7525</a>","short":"P. Bhandari, Localization and Functional Role of Cav2.3 in the Medial Habenula to Interpeduncular Nucleus Pathway, Institute of Science and Technology Austria, 2020.","chicago":"Bhandari, Pradeep. “Localization and Functional Role of Cav2.3 in the Medial Habenula to Interpeduncular Nucleus Pathway.” Institute of Science and Technology Austria, 2020. <a href=\"https://doi.org/10.15479/AT:ISTA:7525\">https://doi.org/10.15479/AT:ISTA:7525</a>.","mla":"Bhandari, Pradeep. <i>Localization and Functional Role of Cav2.3 in the Medial Habenula to Interpeduncular Nucleus Pathway</i>. Institute of Science and Technology Austria, 2020, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:7525\">10.15479/AT:ISTA:7525</a>.","ista":"Bhandari P. 2020. Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway. Institute of Science and Technology Austria.","ieee":"P. Bhandari, “Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway,” Institute of Science and Technology Austria, 2020.","apa":"Bhandari, P. (2020). <i>Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:7525\">https://doi.org/10.15479/AT:ISTA:7525</a>"},"corr_author":"1","user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","degree_awarded":"PhD","ddc":["570"],"year":"2020","doi":"10.15479/AT:ISTA:7525","page":"79","alternative_title":["ISTA Thesis"],"file":[{"creator":"pbhandari","access_level":"open_access","checksum":"4589234fdb12b4ad72273b311723a7b4","file_id":"7538","title":"Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway","date_updated":"2021-03-01T23:30:04Z","file_name":"Pradeep Bhandari Thesis.pdf","date_created":"2020-02-28T08:37:53Z","file_size":9646346,"relation":"main_file","content_type":"application/pdf","embargo":"2021-02-28"},{"content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document","relation":"source_file","file_size":35252164,"embargo_to":"open_access","date_created":"2020-02-28T08:47:14Z","file_name":"Pradeep Bhandari Thesis.docx","date_updated":"2021-03-01T23:30:04Z","file_id":"7539","title":"Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway","checksum":"aa79490553ca0a5c9b6fbcd152e93928","access_level":"closed","creator":"pbhandari"}],"publisher":"Institute of Science and Technology Austria","keyword":["Cav2.3","medial habenula (MHb)","interpeduncular nucleus (IPN)"],"OA_place":"publisher","supervisor":[{"last_name":"Shigemoto","full_name":"Shigemoto, Ryuichi","first_name":"Ryuichi","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-8761-9444"}],"oa":1},{"ec_funded":1,"year":"2020","doi":"10.3390/ijms21186737","quality_controlled":"1","ddc":["570"],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","citation":{"short":"D. Kleindienst, J.-C. Montanaro-Punzengruber, P. Bhandari, M.J. Case, Y. Fukazawa, R. Shigemoto, International Journal of Molecular Sciences 21 (2020).","ama":"Kleindienst D, Montanaro-Punzengruber J-C, Bhandari P, Case MJ, Fukazawa Y, Shigemoto R. Deep learning-assisted high-throughput analysis of freeze-fracture replica images applied to glutamate receptors and calcium channels at hippocampal synapses. <i>International Journal of Molecular Sciences</i>. 2020;21(18). doi:<a href=\"https://doi.org/10.3390/ijms21186737\">10.3390/ijms21186737</a>","mla":"Kleindienst, David, et al. “Deep Learning-Assisted High-Throughput Analysis of Freeze-Fracture Replica Images Applied to Glutamate Receptors and Calcium Channels at Hippocampal Synapses.” <i>International Journal of Molecular Sciences</i>, vol. 21, no. 18, 6737, MDPI, 2020, doi:<a href=\"https://doi.org/10.3390/ijms21186737\">10.3390/ijms21186737</a>.","chicago":"Kleindienst, David, Jacqueline-Claire Montanaro-Punzengruber, Pradeep Bhandari, Matthew J Case, Yugo Fukazawa, and Ryuichi Shigemoto. “Deep Learning-Assisted High-Throughput Analysis of Freeze-Fracture Replica Images Applied to Glutamate Receptors and Calcium Channels at Hippocampal Synapses.” <i>International Journal of Molecular Sciences</i>. MDPI, 2020. <a href=\"https://doi.org/10.3390/ijms21186737\">https://doi.org/10.3390/ijms21186737</a>.","apa":"Kleindienst, D., Montanaro-Punzengruber, J.-C., Bhandari, P., Case, M. J., Fukazawa, Y., &#38; Shigemoto, R. (2020). Deep learning-assisted high-throughput analysis of freeze-fracture replica images applied to glutamate receptors and calcium channels at hippocampal synapses. <i>International Journal of Molecular Sciences</i>. MDPI. <a href=\"https://doi.org/10.3390/ijms21186737\">https://doi.org/10.3390/ijms21186737</a>","ieee":"D. Kleindienst, J.-C. Montanaro-Punzengruber, P. Bhandari, M. J. Case, Y. Fukazawa, and R. Shigemoto, “Deep learning-assisted high-throughput analysis of freeze-fracture replica images applied to glutamate receptors and calcium channels at hippocampal synapses,” <i>International Journal of Molecular Sciences</i>, vol. 21, no. 18. MDPI, 2020.","ista":"Kleindienst D, Montanaro-Punzengruber J-C, Bhandari P, Case MJ, Fukazawa Y, Shigemoto R. 2020. Deep learning-assisted high-throughput analysis of freeze-fracture replica images applied to glutamate receptors and calcium channels at hippocampal synapses. International Journal of Molecular Sciences. 21(18), 6737."},"publication_status":"published","corr_author":"1","article_number":"6737","article_type":"original","isi":1,"related_material":{"record":[{"relation":"dissertation_contains","id":"9562","status":"public"}]},"project":[{"name":"In situ analysis of single channel subunit composition in neurons: physiological implication in synaptic plasticity and behaviour","grant_number":"694539","_id":"25CA28EA-B435-11E9-9278-68D0E5697425","call_identifier":"H2020"},{"_id":"25D32BC0-B435-11E9-9278-68D0E5697425","name":"Mechanism of formation and maintenance of input side-dependent asymmetry in the hippocampus"},{"call_identifier":"H2020","grant_number":"785907","_id":"26436750-B435-11E9-9278-68D0E5697425","name":"Human Brain Project Specific Grant Agreement 2"}],"oa":1,"issue":"18","publisher":"MDPI","intvolume":"        21","file":[{"date_created":"2020-09-21T14:08:58Z","relation":"main_file","file_size":5748456,"content_type":"application/pdf","success":1,"access_level":"open_access","creator":"dernst","checksum":"2e4f62f3cfe945b7391fc3070e5a289f","file_id":"8551","date_updated":"2020-09-21T14:08:58Z","file_name":"2020_JournMolecSciences_Kleindienst.pdf"}],"date_created":"2020-09-20T22:01:35Z","volume":21,"tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"article_processing_charge":"No","type":"journal_article","status":"public","department":[{"_id":"RySh"}],"has_accepted_license":"1","language":[{"iso":"eng"}],"month":"09","fulldoi":"https://doi.org/10.3390/ijms21186737","abstract":[{"text":"The molecular anatomy of synapses defines their characteristics in transmission and plasticity. Precise measurements of the number and distribution of synaptic proteins are important for our understanding of synapse heterogeneity within and between brain regions. Freeze–fracture replica immunogold electron microscopy enables us to analyze them quantitatively on a two-dimensional membrane surface. Here, we introduce Darea software, which utilizes deep learning for analysis of replica images and demonstrate its usefulness for quick measurements of the pre- and postsynaptic areas, density and distribution of gold particles at synapses in a reproducible manner. We used Darea for comparing glutamate receptor and calcium channel distributions between hippocampal CA3-CA1 spine synapses on apical and basal dendrites, which differ in signaling pathways involved in synaptic plasticity. We found that apical synapses express a higher density of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and a stronger increase of AMPA receptors with synaptic size, while basal synapses show a larger increase in N-methyl-D-aspartate (NMDA) receptors with size. Interestingly, AMPA and NMDA receptors are segregated within postsynaptic sites and negatively correlated in density among both apical and basal synapses. In the presynaptic sites, Cav2.1 voltage-gated calcium channels show similar densities in apical and basal synapses with distributions consistent with an exclusion zone model of calcium channel-release site topography.","lang":"eng"}],"day":"14","date_updated":"2026-10-13T22:31:06Z","publication":"International Journal of Molecular Sciences","scopus_import":"1","author":[{"first_name":"David","id":"42E121A4-F248-11E8-B48F-1D18A9856A87","full_name":"Kleindienst, David","last_name":"Kleindienst"},{"full_name":"Montanaro-Punzengruber, Jacqueline-Claire","last_name":"Montanaro-Punzengruber","id":"3786AB44-F248-11E8-B48F-1D18A9856A87","first_name":"Jacqueline-Claire"},{"orcid":"0000-0003-0863-4481","id":"45EDD1BC-F248-11E8-B48F-1D18A9856A87","full_name":"Bhandari, Pradeep","first_name":"Pradeep","last_name":"Bhandari"},{"last_name":"Case","id":"44B7CA5A-F248-11E8-B48F-1D18A9856A87","first_name":"Matthew J","full_name":"Case, Matthew J"},{"last_name":"Fukazawa","full_name":"Fukazawa, Yugo","first_name":"Yugo"},{"orcid":"0000-0001-8761-9444","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","first_name":"Ryuichi","last_name":"Shigemoto","full_name":"Shigemoto, Ryuichi"}],"external_id":{"isi":["000579945300001"]},"_id":"8532","acknowledgement":"This research was funded by Austrian Academy of Sciences, DOC fellowship to D.K., European Research\r\nCouncil Advanced Grant 694539 and European Union Human Brain Project (HBP) SGA2 785907 to R.S.\r\nWe acknowledge Elena Hollergschwandtner for technical support.","oa_version":"Published Version","publication_identifier":{"issn":["1661-6596"],"eissn":["1422-0067"]},"title":"Deep learning-assisted high-throughput analysis of freeze-fracture replica images applied to glutamate receptors and calcium channels at hippocampal synapses","date_published":"2020-09-14T00:00:00Z","file_date_updated":"2020-09-21T14:08:58Z"},{"publication_status":"published","citation":{"ama":"Zenmyo N, Tokumaru H, Uchinomiya S, et al. Optimized reaction pair of the CysHis tag and Ni(II)-NTA probe for highly selective chemical labeling of membrane proteins. <i>Bulletin of the Chemical Society of Japan</i>. 2019;92(5):995-1000. doi:<a href=\"https://doi.org/10.1246/bcsj.20190034\">10.1246/bcsj.20190034</a>","short":"N. Zenmyo, H. Tokumaru, S. Uchinomiya, H. Fuchida, S. Tabata, I. Hamachi, R. Shigemoto, A. Ojida, Bulletin of the Chemical Society of Japan 92 (2019) 995–1000.","ista":"Zenmyo N, Tokumaru H, Uchinomiya S, Fuchida H, Tabata S, Hamachi I, Shigemoto R, Ojida A. 2019. Optimized reaction pair of the CysHis tag and Ni(II)-NTA probe for highly selective chemical labeling of membrane proteins. Bulletin of the Chemical Society of Japan. 92(5), 995–1000.","ieee":"N. Zenmyo <i>et al.</i>, “Optimized reaction pair of the CysHis tag and Ni(II)-NTA probe for highly selective chemical labeling of membrane proteins,” <i>Bulletin of the Chemical Society of Japan</i>, vol. 92, no. 5. Bulletin of the Chemical Society of Japan, pp. 995–1000, 2019.","apa":"Zenmyo, N., Tokumaru, H., Uchinomiya, S., Fuchida, H., Tabata, S., Hamachi, I., … Ojida, A. (2019). Optimized reaction pair of the CysHis tag and Ni(II)-NTA probe for highly selective chemical labeling of membrane proteins. <i>Bulletin of the Chemical Society of Japan</i>. Bulletin of the Chemical Society of Japan. <a href=\"https://doi.org/10.1246/bcsj.20190034\">https://doi.org/10.1246/bcsj.20190034</a>","chicago":"Zenmyo, Naoki, Hiroki Tokumaru, Shohei Uchinomiya, Hirokazu Fuchida, Shigekazu Tabata, Itaru Hamachi, Ryuichi Shigemoto, and Akio Ojida. “Optimized Reaction Pair of the CysHis Tag and Ni(II)-NTA Probe for Highly Selective Chemical Labeling of Membrane Proteins.” <i>Bulletin of the Chemical Society of Japan</i>. Bulletin of the Chemical Society of Japan, 2019. <a href=\"https://doi.org/10.1246/bcsj.20190034\">https://doi.org/10.1246/bcsj.20190034</a>.","mla":"Zenmyo, Naoki, et al. “Optimized Reaction Pair of the CysHis Tag and Ni(II)-NTA Probe for Highly Selective Chemical Labeling of Membrane Proteins.” <i>Bulletin of the Chemical Society of Japan</i>, vol. 92, no. 5, Bulletin of the Chemical Society of Japan, 2019, pp. 995–1000, doi:<a href=\"https://doi.org/10.1246/bcsj.20190034\">10.1246/bcsj.20190034</a>."},"user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","ddc":["570"],"quality_controlled":"1","year":"2019","doi":"10.1246/bcsj.20190034","ec_funded":1,"page":"995-1000","intvolume":"        92","OA_type":"free access","issue":"5","publisher":"Bulletin of the Chemical Society of Japan","isi":1,"project":[{"call_identifier":"H2020","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"}],"oa":1,"article_type":"original","abstract":[{"text":"Chemical labeling of proteins with synthetic molecular probes offers the possibility to probe the functions of proteins of interest in living cells. However, the methods for covalently labeling targeted proteins using complementary peptide tag-probe pairs are still limited, irrespective of the versatility of such pairs in biological research. Herein, we report the new CysHis tag-Ni(II) probe pair for the specific covalent labeling of proteins. A broad-range evaluation of the reactivity profiles of the probe and the CysHis peptide tag afforded a tag-probe pair with an optimized and high labeling selectivity and reactivity. In particular, the labeling specificity of this pair was notably improved compared to the previously reported one. This pair was successfully utilized for the fluorescence imaging of membrane proteins on the surfaces of living cells, demonstrating its potential utility in biological research.","lang":"eng"}],"fulldoi":"https://doi.org/10.1246/bcsj.20190034","date_updated":"2025-09-10T10:37:21Z","day":"15","status":"public","department":[{"_id":"RySh"}],"language":[{"iso":"eng"}],"month":"05","has_accepted_license":"1","article_processing_charge":"No","type":"journal_article","volume":92,"date_created":"2019-07-21T21:59:16Z","date_published":"2019-05-15T00:00:00Z","title":"Optimized reaction pair of the CysHis tag and Ni(II)-NTA probe for highly selective chemical labeling of membrane proteins","publication_identifier":{"issn":["0009-2673"]},"acknowledgement":"his work was supported by the Grant-in-Aid for Scientific Research B (JSPS KAKENHI grant no. JP17H03090 to A. O.); the Scientific Research on Innovative Areas “Chemistry for Multimolecular Crowding Biosystems” (JSPS KAKENHI grant no. JP17H06349 to A. O.); and the European Union (European Research Council Advanced grant no. 694539 and Human Brain Project Ref. 720270 to R. S.). A. O. acknowledges the financial support of the Takeda Science Foundation.","_id":"6659","oa_version":"Published Version","main_file_link":[{"url":"https://doi.org/10.1246/bcsj.20190034","open_access":"1"}],"external_id":{"isi":["000468101800007"]},"scopus_import":"1","publication":"Bulletin of the Chemical Society of Japan","author":[{"last_name":"Zenmyo","full_name":"Zenmyo, Naoki","first_name":"Naoki"},{"first_name":"Hiroki","last_name":"Tokumaru","full_name":"Tokumaru, Hiroki"},{"full_name":"Uchinomiya, Shohei","last_name":"Uchinomiya","first_name":"Shohei"},{"first_name":"Hirokazu","full_name":"Fuchida, Hirokazu","last_name":"Fuchida"},{"id":"4427179E-F248-11E8-B48F-1D18A9856A87","first_name":"Shigekazu","full_name":"Tabata, Shigekazu","last_name":"Tabata"},{"full_name":"Hamachi, Itaru","first_name":"Itaru","last_name":"Hamachi"},{"orcid":"0000-0001-8761-9444","full_name":"Shigemoto, Ryuichi","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","first_name":"Ryuichi","last_name":"Shigemoto"},{"last_name":"Ojida","full_name":"Ojida, Akio","first_name":"Akio"}]},{"citation":{"ieee":"N. Byczkowicz <i>et al.</i>, “HCN channel-mediated neuromodulation can control action potential velocity and fidelity in central axons,” <i>eLife</i>, vol. 8. eLife Sciences Publications, 2019.","apa":"Byczkowicz, N., Eshra, A., Montanaro-Punzengruber, J.-C., Trevisiol, A., Hirrlinger, J., Kole, M. H., … Hallermann, S. (2019). HCN channel-mediated neuromodulation can control action potential velocity and fidelity in central axons. <i>ELife</i>. eLife Sciences Publications. <a href=\"https://doi.org/10.7554/eLife.42766\">https://doi.org/10.7554/eLife.42766</a>","ista":"Byczkowicz N, Eshra A, Montanaro-Punzengruber J-C, Trevisiol A, Hirrlinger J, Kole MH, Shigemoto R, Hallermann S. 2019. HCN channel-mediated neuromodulation can control action potential velocity and fidelity in central axons. eLife. 8, e42766.","mla":"Byczkowicz, Niklas, et al. “HCN Channel-Mediated Neuromodulation Can Control Action Potential Velocity and Fidelity in Central Axons.” <i>ELife</i>, vol. 8, e42766, eLife Sciences Publications, 2019, doi:<a href=\"https://doi.org/10.7554/eLife.42766\">10.7554/eLife.42766</a>.","chicago":"Byczkowicz, Niklas, Abdelmoneim Eshra, Jacqueline-Claire Montanaro-Punzengruber, Andrea Trevisiol, Johannes Hirrlinger, Maarten Hp Kole, Ryuichi Shigemoto, and Stefan Hallermann. “HCN Channel-Mediated Neuromodulation Can Control Action Potential Velocity and Fidelity in Central Axons.” <i>ELife</i>. eLife Sciences Publications, 2019. <a href=\"https://doi.org/10.7554/eLife.42766\">https://doi.org/10.7554/eLife.42766</a>.","ama":"Byczkowicz N, Eshra A, Montanaro-Punzengruber J-C, et al. HCN channel-mediated neuromodulation can control action potential velocity and fidelity in central axons. <i>eLife</i>. 2019;8. doi:<a href=\"https://doi.org/10.7554/eLife.42766\">10.7554/eLife.42766</a>","short":"N. Byczkowicz, A. Eshra, J.-C. Montanaro-Punzengruber, A. Trevisiol, J. Hirrlinger, M.H. Kole, R. Shigemoto, S. Hallermann, ELife 8 (2019)."},"publication_status":"published","user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","quality_controlled":"1","ddc":["570"],"year":"2019","doi":"10.7554/eLife.42766","file":[{"date_updated":"2020-07-14T12:47:42Z","file_name":"2019_eLife_Byczkowicz.pdf","access_level":"open_access","creator":"dernst","checksum":"c350b7861ef0fb537cae8a3232aec016","file_id":"6880","file_size":4008137,"relation":"main_file","content_type":"application/pdf","date_created":"2019-09-16T13:14:33Z"}],"publisher":"eLife Sciences Publications","intvolume":"         8","isi":1,"oa":1,"article_number":"e42766","article_type":"original","fulldoi":"https://doi.org/10.7554/eLife.42766","abstract":[{"lang":"eng","text":"Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels control electrical rhythmicity and excitability in the heart and brain, but the function of HCN channels at the subcellular level in axons remains poorly understood. Here, we show that the action potential conduction velocity in both myelinated and unmyelinated central axons can be bidirectionally modulated by a HCN channel blocker, cyclic adenosine monophosphate (cAMP), and neuromodulators. Recordings from mouse cerebellar mossy fiber boutons show that HCN channels ensure reliable high-frequency firing and are strongly modulated by cAMP (EC50 40 mM; estimated endogenous cAMP concentration 13 mM). In addition, immunogold-electron microscopy revealed HCN2 as the dominating subunit in cerebellar mossy fibers. Computational modeling indicated that HCN2 channels control conduction velocity primarily by altering the resting membrane potential\r\nand are associated with significant metabolic costs. These results suggest that the cAMP-HCN pathway provides neuromodulators with an opportunity to finely tune energy consumption and temporal delays across axons in the brain."}],"day":"09","date_updated":"2026-04-03T09:40:28Z","department":[{"_id":"RySh"}],"status":"public","has_accepted_license":"1","month":"09","language":[{"iso":"eng"}],"type":"journal_article","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"article_processing_charge":"No","date_created":"2019-09-15T22:00:43Z","volume":8,"date_published":"2019-09-09T00:00:00Z","file_date_updated":"2020-07-14T12:47:42Z","publication_identifier":{"eissn":["2050-084X"]},"title":"HCN channel-mediated neuromodulation can control action potential velocity and fidelity in central axons","_id":"6868","oa_version":"Published Version","publication":"eLife","scopus_import":"1","author":[{"last_name":"Byczkowicz","full_name":"Byczkowicz, Niklas","first_name":"Niklas"},{"first_name":"Abdelmoneim","full_name":"Eshra, Abdelmoneim","last_name":"Eshra"},{"last_name":"Montanaro-Punzengruber","full_name":"Montanaro-Punzengruber, Jacqueline-Claire","id":"3786AB44-F248-11E8-B48F-1D18A9856A87","first_name":"Jacqueline-Claire"},{"first_name":"Andrea","full_name":"Trevisiol, Andrea","last_name":"Trevisiol"},{"full_name":"Hirrlinger, Johannes","last_name":"Hirrlinger","first_name":"Johannes"},{"first_name":"Maarten Hp","last_name":"Kole","full_name":"Kole, Maarten Hp"},{"orcid":"0000-0001-8761-9444","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","full_name":"Shigemoto, Ryuichi","last_name":"Shigemoto","first_name":"Ryuichi"},{"full_name":"Hallermann, Stefan","last_name":"Hallermann","first_name":"Stefan"}],"external_id":{"isi":["000485663900001"]}}]