[{"_id":"11943","date_published":"2022-05-09T00:00:00Z","date_created":"2022-08-23T11:07:59Z","oa_version":"Preprint","language":[{"iso":"eng"}],"year":"2022","day":"09","article_processing_charge":"No","month":"05","publication":"bioRxiv","author":[{"first_name":"Philipp","id":"39BDC62C-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-2340-7431","full_name":"Velicky, Philipp","last_name":"Velicky"},{"id":"3FB91342-F248-11E8-B48F-1D18A9856A87","first_name":"Eder","last_name":"Miguel Villalba","full_name":"Miguel Villalba, Eder","orcid":"0000-0001-5665-0430"},{"full_name":"Michalska, Julia M","last_name":"Michalska","orcid":"0000-0003-3862-1235","id":"443DB6DE-F248-11E8-B48F-1D18A9856A87","first_name":"Julia M"},{"first_name":"Donglai","last_name":"Wei","full_name":"Wei, Donglai"},{"first_name":"Zudi","last_name":"Lin","full_name":"Lin, Zudi"},{"first_name":"Jake","id":"63836096-4690-11EA-BD4E-32803DDC885E","orcid":"0000-0002-8698-3823","last_name":"Watson","full_name":"Watson, Jake"},{"first_name":"Jakob","last_name":"Troidl","full_name":"Troidl, Jakob"},{"first_name":"Johanna","full_name":"Beyer, Johanna","last_name":"Beyer"},{"first_name":"Yoav","id":"43DF3136-F248-11E8-B48F-1D18A9856A87","last_name":"Ben Simon","full_name":"Ben Simon, Yoav"},{"id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87","first_name":"Christoph M","full_name":"Sommer, Christoph M","last_name":"Sommer","orcid":"0000-0003-1216-9105"},{"orcid":"0000-0003-0201-2315","last_name":"Jahr","full_name":"Jahr, Wiebke","first_name":"Wiebke","id":"425C1CE8-F248-11E8-B48F-1D18A9856A87"},{"id":"9ac8f577-2357-11eb-997a-e566c5550886","first_name":"Alban","last_name":"Cenameri","full_name":"Cenameri, Alban"},{"first_name":"Johannes","last_name":"Broichhagen","full_name":"Broichhagen, Johannes"},{"full_name":"Grant, Seth G. N.","last_name":"Grant","first_name":"Seth G. N."},{"id":"353C1B58-F248-11E8-B48F-1D18A9856A87","first_name":"Peter M","last_name":"Jonas","full_name":"Jonas, Peter M","orcid":"0000-0001-5001-4804"},{"last_name":"Novarino","full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178","first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Pfister","full_name":"Pfister, Hanspeter","first_name":"Hanspeter"},{"first_name":"Bernd","id":"49876194-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-6511-9385","last_name":"Bickel","full_name":"Bickel, Bernd"},{"orcid":"0000-0001-8559-3973","last_name":"Danzl","full_name":"Danzl, Johann G","id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","first_name":"Johann G"}],"department":[{"_id":"PeJo"},{"_id":"GaNo"},{"_id":"BeBi"},{"_id":"JoDa"}],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publication_status":"draft","type":"preprint","related_material":{"record":[{"relation":"later_version","id":"13267","status":"public"},{"status":"public","id":"12470","relation":"dissertation_contains"}]},"title":"Saturated reconstruction of living brain tissue","abstract":[{"text":"Complex wiring between neurons underlies the information-processing network enabling all brain functions, including cognition and memory. For understanding how the network is structured, processes information, and changes over time, comprehensive visualization of the architecture of living brain tissue with its cellular and molecular components would open up major opportunities. However, electron microscopy (EM) provides nanometre-scale resolution required for full <jats:italic>in-silico</jats:italic> reconstruction<jats:sup>1–5</jats:sup>, yet is limited to fixed specimens and static representations. Light microscopy allows live observation, with super-resolution approaches<jats:sup>6–12</jats:sup> facilitating nanoscale visualization, but comprehensive 3D-reconstruction of living brain tissue has been hindered by tissue photo-burden, photobleaching, insufficient 3D-resolution, and inadequate signal-to-noise ratio (SNR). Here we demonstrate saturated reconstruction of living brain tissue. We developed an integrated imaging and analysis technology, adapting stimulated emission depletion (STED) microscopy<jats:sup>6,13</jats:sup> in extracellularly labelled tissue<jats:sup>14</jats:sup> for high SNR and near-isotropic resolution. Centrally, a two-stage deep-learning approach leveraged previously obtained information on sample structure to drastically reduce photo-burden and enable automated volumetric reconstruction down to single synapse level. Live reconstruction provides unbiased analysis of tissue architecture across time in relation to functional activity and targeted activation, and contextual understanding of molecular labelling. This adoptable technology will facilitate novel insights into the dynamic functional architecture of living brain tissue.","lang":"eng"}],"main_file_link":[{"url":"https://doi.org/10.1101/2022.03.16.484431","open_access":"1"}],"citation":{"apa":"Velicky, P., Miguel Villalba, E., Michalska, J. M., Wei, D., Lin, Z., Watson, J., … Danzl, J. G. (n.d.). Saturated reconstruction of living brain tissue. <i>bioRxiv</i>. <a href=\"https://doi.org/10.1101/2022.03.16.484431\">https://doi.org/10.1101/2022.03.16.484431</a>","ama":"Velicky P, Miguel Villalba E, Michalska JM, et al. Saturated reconstruction of living brain tissue. <i>bioRxiv</i>. doi:<a href=\"https://doi.org/10.1101/2022.03.16.484431\">10.1101/2022.03.16.484431</a>","short":"P. Velicky, E. Miguel Villalba, J.M. Michalska, D. Wei, Z. Lin, J. Watson, J. Troidl, J. Beyer, Y. Ben Simon, C.M. Sommer, W. Jahr, A. Cenameri, J. Broichhagen, S.G.N. Grant, P.M. Jonas, G. Novarino, H. Pfister, B. Bickel, J.G. Danzl, BioRxiv (n.d.).","mla":"Velicky, Philipp, et al. “Saturated Reconstruction of Living Brain Tissue.” <i>BioRxiv</i>, doi:<a href=\"https://doi.org/10.1101/2022.03.16.484431\">10.1101/2022.03.16.484431</a>.","chicago":"Velicky, Philipp, Eder Miguel Villalba, Julia M Michalska, Donglai Wei, Zudi Lin, Jake Watson, Jakob Troidl, et al. “Saturated Reconstruction of Living Brain Tissue.” <i>BioRxiv</i>, n.d. <a href=\"https://doi.org/10.1101/2022.03.16.484431\">https://doi.org/10.1101/2022.03.16.484431</a>.","ieee":"P. Velicky <i>et al.</i>, “Saturated reconstruction of living brain tissue,” <i>bioRxiv</i>. .","ista":"Velicky P, Miguel Villalba E, Michalska JM, Wei D, Lin Z, Watson J, Troidl J, Beyer J, Ben Simon Y, Sommer CM, Jahr W, Cenameri A, Broichhagen J, Grant SGN, Jonas PM, Novarino G, Pfister H, Bickel B, Danzl JG. Saturated reconstruction of living brain tissue. bioRxiv, <a href=\"https://doi.org/10.1101/2022.03.16.484431\">10.1101/2022.03.16.484431</a>."},"corr_author":"1","status":"public","date_updated":"2026-08-28T22:31:04Z","doi":"10.1101/2022.03.16.484431","OA_place":"repository","oa":1,"das_tickbox":"1"},{"main_file_link":[{"url":"https://doi.org/10.1101/2022.08.17.504272","open_access":"1"}],"corr_author":"1","citation":{"short":"J.M. Michalska, J. Lyudchik, P. Velicky, H. Korinkova, J. Watson, A. Cenameri, C.M. Sommer, A. Venturino, K. Roessler, T. Czech, S. Siegert, G. Novarino, P.M. Jonas, J.G. Danzl, BioRxiv (n.d.).","apa":"Michalska, J. M., Lyudchik, J., Velicky, P., Korinkova, H., Watson, J., Cenameri, A., … Danzl, J. G. (n.d.). Uncovering brain tissue architecture across scales with super-resolution light microscopy. <i>bioRxiv</i>. <a href=\"https://doi.org/10.1101/2022.08.17.504272\">https://doi.org/10.1101/2022.08.17.504272</a>","ama":"Michalska JM, Lyudchik J, Velicky P, et al. Uncovering brain tissue architecture across scales with super-resolution light microscopy. <i>bioRxiv</i>. doi:<a href=\"https://doi.org/10.1101/2022.08.17.504272\">10.1101/2022.08.17.504272</a>","ista":"Michalska JM, Lyudchik J, Velicky P, Korinkova H, Watson J, Cenameri A, Sommer CM, Venturino A, Roessler K, Czech T, Siegert S, Novarino G, Jonas PM, Danzl JG. Uncovering brain tissue architecture across scales with super-resolution light microscopy. bioRxiv, <a href=\"https://doi.org/10.1101/2022.08.17.504272\">10.1101/2022.08.17.504272</a>.","mla":"Michalska, Julia M., et al. “Uncovering Brain Tissue Architecture across Scales with Super-Resolution Light Microscopy.” <i>BioRxiv</i>, doi:<a href=\"https://doi.org/10.1101/2022.08.17.504272\">10.1101/2022.08.17.504272</a>.","ieee":"J. M. Michalska <i>et al.</i>, “Uncovering brain tissue architecture across scales with super-resolution light microscopy,” <i>bioRxiv</i>. .","chicago":"Michalska, Julia M, Julia Lyudchik, Philipp Velicky, Hana Korinkova, Jake Watson, Alban Cenameri, Christoph M Sommer, et al. “Uncovering Brain Tissue Architecture across Scales with Super-Resolution Light Microscopy.” <i>BioRxiv</i>, n.d. <a href=\"https://doi.org/10.1101/2022.08.17.504272\">https://doi.org/10.1101/2022.08.17.504272</a>."},"related_material":{"record":[{"status":"public","id":"12470","relation":"dissertation_contains"}]},"abstract":[{"text":"Mapping the complex and dense arrangement of cells and their connectivity in brain tissue demands nanoscale spatial resolution imaging. Super-resolution optical microscopy excels at visualizing specific molecules and individual cells but fails to provide tissue context. Here we developed Comprehensive Analysis of Tissues across Scales (CATS), a technology to densely map brain tissue architecture from millimeter regional to nanoscopic synaptic scales in diverse chemically fixed brain preparations, including rodent and human. CATS leverages fixation-compatible extracellular labeling and advanced optical readout, in particular stimulated-emission depletion and expansion microscopy, to comprehensively delineate cellular structures. It enables 3D-reconstructing single synapses and mapping synaptic connectivity by identification and tailored analysis of putative synaptic cleft regions. Applying CATS to the hippocampal mossy fiber circuitry, we demonstrate its power to reveal the system’s molecularly informed ultrastructure across spatial scales and assess local connectivity by reconstructing and quantifying the synaptic input and output structure of identified neurons.","lang":"eng"}],"title":"Uncovering brain tissue architecture across scales with super-resolution light microscopy","oa":1,"das_tickbox":"1","date_updated":"2026-08-28T22:31:04Z","status":"public","doi":"10.1101/2022.08.17.504272","oa_version":"Preprint","year":"2022","language":[{"iso":"eng"}],"date_published":"2022-08-18T00:00:00Z","_id":"11950","date_created":"2022-08-24T08:24:52Z","publication":"bioRxiv","month":"08","type":"preprint","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publication_status":"draft","department":[{"_id":"SaSi"},{"_id":"GaNo"},{"_id":"PeJo"},{"_id":"JoDa"}],"author":[{"orcid":"0000-0003-3862-1235","last_name":"Michalska","full_name":"Michalska, Julia M","first_name":"Julia M","id":"443DB6DE-F248-11E8-B48F-1D18A9856A87"},{"id":"46E28B80-F248-11E8-B48F-1D18A9856A87","first_name":"Julia","last_name":"Lyudchik","full_name":"Lyudchik, Julia"},{"first_name":"Philipp","id":"39BDC62C-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-2340-7431","full_name":"Velicky, Philipp","last_name":"Velicky"},{"id":"ee3cb6ca-ec98-11ea-ae11-ff703e2254ed","first_name":"Hana","last_name":"Korinkova","full_name":"Korinkova, Hana"},{"last_name":"Watson","full_name":"Watson, Jake","orcid":"0000-0002-8698-3823","first_name":"Jake","id":"63836096-4690-11EA-BD4E-32803DDC885E"},{"last_name":"Cenameri","full_name":"Cenameri, Alban","first_name":"Alban","id":"9ac8f577-2357-11eb-997a-e566c5550886"},{"orcid":"0000-0003-1216-9105","full_name":"Sommer, Christoph M","last_name":"Sommer","first_name":"Christoph M","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87"},{"orcid":"0000-0003-2356-9403","full_name":"Venturino, Alessandro","last_name":"Venturino","first_name":"Alessandro","id":"41CB84B2-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Roessler, Karl","last_name":"Roessler","first_name":"Karl"},{"full_name":"Czech, Thomas","last_name":"Czech","first_name":"Thomas"},{"orcid":"0000-0001-8635-0877","last_name":"Siegert","full_name":"Siegert, Sandra","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","first_name":"Sandra"},{"first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","last_name":"Novarino","full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178"},{"id":"353C1B58-F248-11E8-B48F-1D18A9856A87","first_name":"Peter M","orcid":"0000-0001-5001-4804","full_name":"Jonas, Peter M","last_name":"Jonas"},{"first_name":"Johann G","id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","last_name":"Danzl","full_name":"Danzl, Johann G","orcid":"0000-0001-8559-3973"}],"article_processing_charge":"No","day":"18"},{"date_published":"2021-02-22T00:00:00Z","_id":"15273","external_id":{"pmid":["33616036"]},"pmid":1,"license":"https://creativecommons.org/licenses/by/4.0/","date_created":"2024-04-03T07:58:11Z","file_date_updated":"2024-04-09T11:13:07Z","year":"2021","article_processing_charge":"Yes","day":"22","publication":"eLife","type":"journal_article","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","file":[{"file_id":"15307","checksum":"bbd4de2e54b7fbc11fba14f59e87fe3f","content_type":"application/pdf","success":1,"date_updated":"2024-04-09T11:13:07Z","file_name":"2021_eLife_Balmer.pdf","creator":"dernst","access_level":"open_access","file_size":6997954,"relation":"main_file","date_created":"2024-04-09T11:13:07Z"}],"publisher":"eLife Sciences Publications","quality_controlled":"1","title":"Incomplete removal of extracellular glutamate controls synaptic transmission and integration at a cerebellar synapse","abstract":[{"lang":"eng","text":"Synapses of glutamatergic mossy fibers (MFs) onto cerebellar unipolar brush cells (UBCs) generate slow excitatory (ON) or inhibitory (OFF) postsynaptic responses dependent on the complement of glutamate receptors expressed on the UBC’s large dendritic brush. Using mouse brain slice recording and computational modeling of synaptic transmission, we found that substantial glutamate is maintained in the UBC synaptic cleft, sufficient to modify spontaneous firing in OFF UBCs and tonically desensitize AMPARs of ON UBCs. The source of this ambient glutamate was spontaneous, spike-independent exocytosis from the MF terminal, and its level was dependent on activity of glutamate transporters EAAT1–2. Increasing levels of ambient glutamate shifted the polarity of evoked synaptic responses in ON UBCs and altered the phase of responses to in vivo-like synaptic activity. Unlike classical fast synapses, receptors at the UBC synapse are virtually always exposed to a significant level of glutamate, which varies in a graded manner during transmission."}],"publication_identifier":{"issn":["2050-084X"]},"status":"public","date_updated":"2024-04-09T11:15:01Z","doi":"10.7554/elife.63819","keyword":["General Immunology and Microbiology","General Biochemistry","Genetics and Molecular Biology","General Medicine","General Neuroscience"],"oa":1,"tmp":{"image":"/images/cc_by.png","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"article_type":"original","oa_version":"Published Version","language":[{"iso":"eng"}],"ddc":["570"],"intvolume":"        10","month":"02","volume":10,"publication_status":"published","department":[{"_id":"PeJo"}],"author":[{"full_name":"Balmer, Timothy S","last_name":"Balmer","first_name":"Timothy S"},{"id":"4305C450-F248-11E8-B48F-1D18A9856A87","first_name":"Carolina","last_name":"Borges Merjane","full_name":"Borges Merjane, Carolina","orcid":"0000-0003-0005-401X"},{"full_name":"Trussell, Laurence O","last_name":"Trussell","first_name":"Laurence O"}],"has_accepted_license":"1","article_number":"e63819","citation":{"short":"T.S. Balmer, C. Borges Merjane, L.O. Trussell, ELife 10 (2021).","ama":"Balmer TS, Borges Merjane C, Trussell LO. Incomplete removal of extracellular glutamate controls synaptic transmission and integration at a cerebellar synapse. <i>eLife</i>. 2021;10. doi:<a href=\"https://doi.org/10.7554/elife.63819\">10.7554/elife.63819</a>","apa":"Balmer, T. S., Borges Merjane, C., &#38; Trussell, L. O. (2021). Incomplete removal of extracellular glutamate controls synaptic transmission and integration at a cerebellar synapse. <i>ELife</i>. eLife Sciences Publications. <a href=\"https://doi.org/10.7554/elife.63819\">https://doi.org/10.7554/elife.63819</a>","ista":"Balmer TS, Borges Merjane C, Trussell LO. 2021. Incomplete removal of extracellular glutamate controls synaptic transmission and integration at a cerebellar synapse. eLife. 10, e63819.","chicago":"Balmer, Timothy S, Carolina Borges Merjane, and Laurence O Trussell. “Incomplete Removal of Extracellular Glutamate Controls Synaptic Transmission and Integration at a Cerebellar Synapse.” <i>ELife</i>. eLife Sciences Publications, 2021. <a href=\"https://doi.org/10.7554/elife.63819\">https://doi.org/10.7554/elife.63819</a>.","ieee":"T. S. Balmer, C. Borges Merjane, and L. O. Trussell, “Incomplete removal of extracellular glutamate controls synaptic transmission and integration at a cerebellar synapse,” <i>eLife</i>, vol. 10. eLife Sciences Publications, 2021.","mla":"Balmer, Timothy S., et al. “Incomplete Removal of Extracellular Glutamate Controls Synaptic Transmission and Integration at a Cerebellar Synapse.” <i>ELife</i>, vol. 10, e63819, eLife Sciences Publications, 2021, doi:<a href=\"https://doi.org/10.7554/elife.63819\">10.7554/elife.63819</a>."}},{"year":"2021","file_date_updated":"2021-04-19T08:30:22Z","license":"https://creativecommons.org/licenses/by-nc-nd/4.0/","pmid":1,"date_created":"2021-04-18T22:01:39Z","_id":"9329","external_id":{"pmid":["33711356"],"isi":["000661088500005"]},"acknowledged_ssus":[{"_id":"SSU"}],"date_published":"2021-03-09T00:00:00Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","type":"journal_article","publication":"Journal of Neuroscience Methods","day":"09","article_processing_charge":"Yes (via OA deal)","publication_identifier":{"eissn":["1872-678X"],"issn":["0165-0270"]},"title":"MOD: A novel machine-learning optimal-filtering method for accurate and efficient detection of subthreshold synaptic events in vivo","quality_controlled":"1","abstract":[{"text":"Background: To understand information coding in single neurons, it is necessary to analyze subthreshold synaptic events, action potentials (APs), and their interrelation in different behavioral states. However, detecting excitatory postsynaptic potentials (EPSPs) or currents (EPSCs) in behaving animals remains challenging, because of unfavorable signal-to-noise ratio, high frequency, fluctuating amplitude, and variable time course of synaptic events.\r\nNew method: We developed a method for synaptic event detection, termed MOD (Machine-learning Optimal-filtering Detection-procedure), which combines concepts of supervised machine learning and optimal Wiener filtering. Experts were asked to manually score short epochs of data. The algorithm was trained to obtain the optimal filter coefficients of a Wiener filter and the optimal detection threshold. Scored and unscored data were then processed with the optimal filter, and events were detected as peaks above threshold.\r\nResults: We challenged MOD with EPSP traces in vivo in mice during spatial navigation and EPSC traces in vitro in slices under conditions of enhanced transmitter release. The area under the curve (AUC) of the receiver operating characteristics (ROC) curve was, on average, 0.894 for in vivo and 0.969 for in vitro data sets, indicating high detection accuracy and efficiency.\r\nComparison with existing methods: When benchmarked using a (1 − AUC)−1 metric, MOD outperformed previous methods (template-fit, deconvolution, and Bayesian methods) by an average factor of 3.13 for in vivo data sets, but showed comparable (template-fit, deconvolution) or higher (Bayesian) computational efficacy.\r\nConclusions: MOD may become an important new tool for large-scale, real-time analysis of synaptic activity.","lang":"eng"}],"publisher":"Elsevier","file":[{"success":1,"checksum":"2a5800d91b96d08b525e17319dcd5e44","file_id":"9339","content_type":"application/pdf","date_updated":"2021-04-19T08:30:22Z","file_name":"2021_JourNeuroscienceMeth_Zhang.pdf","relation":"main_file","date_created":"2021-04-19T08:30:22Z","file_size":6924738,"access_level":"open_access","creator":"dernst"}],"tmp":{"short":"CC BY-NC-ND (4.0)","image":"/images/cc_by_nc_nd.png","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode"},"article_type":"original","oa":1,"date_updated":"2025-06-12T06:39:15Z","status":"public","doi":"10.1016/j.jneumeth.2021.109125","project":[{"call_identifier":"H2020","_id":"25B7EB9E-B435-11E9-9278-68D0E5697425","grant_number":"692692","name":"Biophysics and circuit function of a giant cortical glutamatergic synapse"},{"call_identifier":"FWF","_id":"25C5A090-B435-11E9-9278-68D0E5697425","grant_number":"Z00312","name":"Synaptic communication in neuronal microcircuits"}],"language":[{"iso":"eng"}],"oa_version":"Published Version","department":[{"_id":"PeJo"},{"_id":"ScienComp"}],"author":[{"id":"423EC9C2-F248-11E8-B48F-1D18A9856A87","first_name":"Xiaomin","last_name":"Zhang","full_name":"Zhang, Xiaomin"},{"last_name":"Schlögl","full_name":"Schlögl, Alois","orcid":"0000-0002-5621-8100","first_name":"Alois","id":"45BF87EE-F248-11E8-B48F-1D18A9856A87"},{"id":"3AE48E0A-F248-11E8-B48F-1D18A9856A87","first_name":"David H","orcid":"0000-0001-7577-1676","full_name":"Vandael, David H","last_name":"Vandael"},{"orcid":"0000-0001-5001-4804","full_name":"Jonas, Peter M","last_name":"Jonas","id":"353C1B58-F248-11E8-B48F-1D18A9856A87","first_name":"Peter M"}],"isi":1,"publication_status":"published","volume":357,"month":"03","scopus_import":"1","ddc":["570"],"intvolume":"       357","acknowledgement":"This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement number 692692 to P.J.) and the Fond zur Förderung der Wissenschaftlichen Forschung (Z 312-B27, Wittgenstein award to P.J.). We thank Drs. Jozsef Csicsvari, Christoph Lampert, and Federico Stella for critically reading previous manuscript versions. We are also grateful to Drs. Josh Merel and Ben Shababo for their help with applying the Bayesian detection method to our data. We also thank Florian Marr for technical assistance, Eleftheria Kralli-Beller for manuscript editing, and the Scientific Service Units of IST Austria for efficient support.","citation":{"ama":"Zhang X, Schlögl A, Vandael DH, Jonas PM. MOD: A novel machine-learning optimal-filtering method for accurate and efficient detection of subthreshold synaptic events in vivo. <i>Journal of Neuroscience Methods</i>. 2021;357(6). doi:<a href=\"https://doi.org/10.1016/j.jneumeth.2021.109125\">10.1016/j.jneumeth.2021.109125</a>","apa":"Zhang, X., Schlögl, A., Vandael, D. H., &#38; Jonas, P. M. (2021). MOD: A novel machine-learning optimal-filtering method for accurate and efficient detection of subthreshold synaptic events in vivo. <i>Journal of Neuroscience Methods</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.jneumeth.2021.109125\">https://doi.org/10.1016/j.jneumeth.2021.109125</a>","short":"X. Zhang, A. Schlögl, D.H. Vandael, P.M. Jonas, Journal of Neuroscience Methods 357 (2021).","ieee":"X. Zhang, A. Schlögl, D. H. Vandael, and P. M. Jonas, “MOD: A novel machine-learning optimal-filtering method for accurate and efficient detection of subthreshold synaptic events in vivo,” <i>Journal of Neuroscience Methods</i>, vol. 357, no. 6. Elsevier, 2021.","chicago":"Zhang, Xiaomin, Alois Schlögl, David H Vandael, and Peter M Jonas. “MOD: A Novel Machine-Learning Optimal-Filtering Method for Accurate and Efficient Detection of Subthreshold Synaptic Events in Vivo.” <i>Journal of Neuroscience Methods</i>. Elsevier, 2021. <a href=\"https://doi.org/10.1016/j.jneumeth.2021.109125\">https://doi.org/10.1016/j.jneumeth.2021.109125</a>.","mla":"Zhang, Xiaomin, et al. “MOD: A Novel Machine-Learning Optimal-Filtering Method for Accurate and Efficient Detection of Subthreshold Synaptic Events in Vivo.” <i>Journal of Neuroscience Methods</i>, vol. 357, no. 6, 109125, Elsevier, 2021, doi:<a href=\"https://doi.org/10.1016/j.jneumeth.2021.109125\">10.1016/j.jneumeth.2021.109125</a>.","ista":"Zhang X, Schlögl A, Vandael DH, Jonas PM. 2021. MOD: A novel machine-learning optimal-filtering method for accurate and efficient detection of subthreshold synaptic events in vivo. Journal of Neuroscience Methods. 357(6), 109125."},"article_number":"109125","issue":"6","has_accepted_license":"1","ec_funded":1},{"acknowledgement":"We thank members of the Greger laboratory, B. Herguedas, J. Krieger and J.-N. Dohrke for comments on the manuscript; J. Krieger and J.-N. Dohrke for discussion, J. Krieger for help with the normal mode analysis, B. Köhegyi for help with cryo-EM imaging, V. Chang and K. Suzuki for helping to generate the CNIH2-1D4-HA stable cell line, M. Carvalho for assistance at early stages of this project, the LMB scientific computing and the cryo-EM facility for support, P. Emsley for help with model building, T. Nakane for helpful comments with RELION 3.1 and R. Warshamanage for helping with EMDA cryo-EM-map processing. We acknowledge the Diamond Light Source for access and support of the Cryo-EM facilities at the UK national electron bio10 imaging centre (eBIC), proposal EM17434, funded by the Wellcome Trust, MRC and BBSRC. This work was supported by grants from the Medical Research Council, as part of United Kingdom Research and Innovation (also known as UK Research and Innovation) (MC_U105174197) and BBSRC (BB/N002113/1) to I.H.G.","intvolume":"       594","ddc":["570"],"scopus_import":"1","month":"06","volume":594,"isi":1,"publication_status":"published","author":[{"first_name":"Danyang","last_name":"Zhang","full_name":"Zhang, Danyang"},{"full_name":"Watson, Jake","last_name":"Watson","orcid":"0000-0002-8698-3823","first_name":"Jake","id":"63836096-4690-11EA-BD4E-32803DDC885E"},{"full_name":"Matthews, Peter M.","last_name":"Matthews","first_name":"Peter M."},{"full_name":"Cais, Ondrej","last_name":"Cais","first_name":"Ondrej"},{"first_name":"Ingo H.","full_name":"Greger, Ingo H.","last_name":"Greger"}],"department":[{"_id":"PeJo"}],"page":"454-458","oa_version":"Published Version","language":[{"iso":"eng"}],"citation":{"short":"D. Zhang, J. Watson, P.M. Matthews, O. Cais, I.H. Greger, Nature 594 (2021) 454–458.","ama":"Zhang D, Watson J, Matthews PM, Cais O, Greger IH. Gating and modulation of a hetero-octameric AMPA glutamate receptor. <i>Nature</i>. 2021;594:454-458. doi:<a href=\"https://doi.org/10.1038/s41586-021-03613-0\">10.1038/s41586-021-03613-0</a>","apa":"Zhang, D., Watson, J., Matthews, P. M., Cais, O., &#38; Greger, I. H. (2021). Gating and modulation of a hetero-octameric AMPA glutamate receptor. <i>Nature</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41586-021-03613-0\">https://doi.org/10.1038/s41586-021-03613-0</a>","ista":"Zhang D, Watson J, Matthews PM, Cais O, Greger IH. 2021. Gating and modulation of a hetero-octameric AMPA glutamate receptor. Nature. 594, 454–458.","chicago":"Zhang, Danyang, Jake Watson, Peter M. Matthews, Ondrej Cais, and Ingo H. Greger. “Gating and Modulation of a Hetero-Octameric AMPA Glutamate Receptor.” <i>Nature</i>. Springer Nature, 2021. <a href=\"https://doi.org/10.1038/s41586-021-03613-0\">https://doi.org/10.1038/s41586-021-03613-0</a>.","ieee":"D. Zhang, J. Watson, P. M. Matthews, O. Cais, and I. H. Greger, “Gating and modulation of a hetero-octameric AMPA glutamate receptor,” <i>Nature</i>, vol. 594. Springer Nature, pp. 454–458, 2021.","mla":"Zhang, Danyang, et al. “Gating and Modulation of a Hetero-Octameric AMPA Glutamate Receptor.” <i>Nature</i>, vol. 594, Springer Nature, 2021, pp. 454–58, doi:<a href=\"https://doi.org/10.1038/s41586-021-03613-0\">10.1038/s41586-021-03613-0</a>."},"article_processing_charge":"No","day":"02","publication":"Nature","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","type":"journal_article","date_published":"2021-06-02T00:00:00Z","external_id":{"pmid":["34079129"],"isi":["000657238100003"]},"_id":"9549","pmid":1,"date_created":"2021-06-13T22:01:33Z","year":"2021","date_updated":"2026-06-18T19:54:04Z","doi":"10.1038/s41586-021-03613-0","status":"public","oa":1,"article_type":"original","publisher":"Springer Nature","abstract":[{"lang":"eng","text":"AMPA receptors (AMPARs) mediate the majority of excitatory transmission in the brain and enable the synaptic plasticity that underlies learning1. A diverse array of AMPAR signalling complexes are established by receptor auxiliary subunits, which associate with the AMPAR in various combinations to modulate trafficking, gating and synaptic strength2. However, their mechanisms of action are poorly understood. Here we determine cryo-electron microscopy structures of the heteromeric GluA1–GluA2 receptor assembled with both TARP-γ8 and CNIH2, the predominant AMPAR complex in the forebrain, in both resting and active states. Two TARP-γ8 and two CNIH2 subunits insert at distinct sites beneath the ligand-binding domains of the receptor, with site-specific lipids shaping each interaction and affecting the gating regulation of the AMPARs. Activation of the receptor leads to asymmetry between GluA1 and GluA2 along the ion conduction path and an outward expansion of the channel triggers counter-rotations of both auxiliary subunit pairs, promoting the active-state conformation. In addition, both TARP-γ8 and CNIH2 pivot towards the pore exit upon activation, extending their reach for cytoplasmic receptor elements. CNIH2 achieves this through its uniquely extended M2 helix, which has transformed this endoplasmic reticulum-export factor into a powerful AMPAR modulator that is capable of providing hippocampal pyramidal neurons with their integrative synaptic properties. "}],"quality_controlled":"1","title":"Gating and modulation of a hetero-octameric AMPA glutamate receptor","main_file_link":[{"open_access":"1","url":"https://doi.org/10.1038/s41586-021-03613-0"}],"publication_identifier":{"issn":["0028-0836"],"eissn":["1476-4687"]}},{"acknowledgement":"We thank Drs. Carolina Borges-Merjane and Jose Guzman for critically reading the manuscript, and Pablo Castillo for discussions. We are grateful to Alois Schlögl for help with analysis, Florian Marr for excellent technical assistance and cell reconstruction, Christina Altmutter for technical help, Eleftheria Kralli-Beller for manuscript editing, and the Scientific Service Units of IST Austria for support. This project received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 692692) and the Fond zur Förderung der Wissenschaftlichen Forschung (Z 312-B27, Wittgenstein award), both to P.J.","intvolume":"        12","ddc":["570"],"scopus_import":"1","month":"05","volume":12,"publication_status":"published","isi":1,"department":[{"_id":"PeJo"}],"author":[{"full_name":"Vandael, David H","last_name":"Vandael","orcid":"0000-0001-7577-1676","id":"3AE48E0A-F248-11E8-B48F-1D18A9856A87","first_name":"David H"},{"last_name":"Okamoto","full_name":"Okamoto, Yuji","orcid":"0000-0003-0408-6094","first_name":"Yuji","id":"3337E116-F248-11E8-B48F-1D18A9856A87"},{"id":"353C1B58-F248-11E8-B48F-1D18A9856A87","first_name":"Peter M","orcid":"0000-0001-5001-4804","last_name":"Jonas","full_name":"Jonas, Peter M"}],"oa_version":"Published Version","language":[{"iso":"eng"}],"OA_place":"publisher","ec_funded":1,"related_material":{"link":[{"description":"News on IST Homepage","url":"https://ist.ac.at/en/news/synaptic-transmission-not-a-one-way-street/","relation":"press_release"}]},"has_accepted_license":"1","issue":"1","OA_type":"gold","article_number":"2912","corr_author":"1","citation":{"short":"D.H. Vandael, Y. Okamoto, P.M. Jonas, Nature Communications 12 (2021).","apa":"Vandael, D. H., Okamoto, Y., &#38; Jonas, P. M. (2021). Transsynaptic modulation of presynaptic short-term plasticity in hippocampal mossy fiber synapses. <i>Nature Communications</i>. Springer. <a href=\"https://doi.org/10.1038/s41467-021-23153-5\">https://doi.org/10.1038/s41467-021-23153-5</a>","ama":"Vandael DH, Okamoto Y, Jonas PM. Transsynaptic modulation of presynaptic short-term plasticity in hippocampal mossy fiber synapses. <i>Nature Communications</i>. 2021;12(1). doi:<a href=\"https://doi.org/10.1038/s41467-021-23153-5\">10.1038/s41467-021-23153-5</a>","ista":"Vandael DH, Okamoto Y, Jonas PM. 2021. Transsynaptic modulation of presynaptic short-term plasticity in hippocampal mossy fiber synapses. Nature Communications. 12(1), 2912.","mla":"Vandael, David H., et al. “Transsynaptic Modulation of Presynaptic Short-Term Plasticity in Hippocampal Mossy Fiber Synapses.” <i>Nature Communications</i>, vol. 12, no. 1, 2912, Springer, 2021, doi:<a href=\"https://doi.org/10.1038/s41467-021-23153-5\">10.1038/s41467-021-23153-5</a>.","chicago":"Vandael, David H, Yuji Okamoto, and Peter M Jonas. “Transsynaptic Modulation of Presynaptic Short-Term Plasticity in Hippocampal Mossy Fiber Synapses.” <i>Nature Communications</i>. Springer, 2021. <a href=\"https://doi.org/10.1038/s41467-021-23153-5\">https://doi.org/10.1038/s41467-021-23153-5</a>.","ieee":"D. H. Vandael, Y. Okamoto, and P. M. Jonas, “Transsynaptic modulation of presynaptic short-term plasticity in hippocampal mossy fiber synapses,” <i>Nature Communications</i>, vol. 12, no. 1. Springer, 2021."},"article_processing_charge":"Yes","day":"18","publication":"Nature Communications","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","type":"journal_article","date_published":"2021-05-18T00:00:00Z","_id":"9778","acknowledged_ssus":[{"_id":"SSU"}],"external_id":{"pmid":["34006874"],"isi":["000655481800014"]},"date_created":"2021-08-06T07:22:55Z","pmid":1,"file_date_updated":"2021-12-17T11:34:50Z","year":"2021","project":[{"call_identifier":"H2020","grant_number":"692692","name":"Biophysics and circuit function of a giant cortical glutamatergic synapse","_id":"25B7EB9E-B435-11E9-9278-68D0E5697425"},{"grant_number":"Z00312","name":"Synaptic communication in neuronal microcircuits","_id":"25C5A090-B435-11E9-9278-68D0E5697425","call_identifier":"FWF"}],"status":"public","keyword":["general physics and astronomy","general biochemistry","genetics and molecular biology","general chemistry"],"doi":"10.1038/s41467-021-23153-5","date_updated":"2025-06-12T06:28:45Z","oa":1,"article_type":"original","tmp":{"image":"/images/cc_by.png","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"file":[{"relation":"main_file","date_created":"2021-12-17T11:34:50Z","access_level":"open_access","creator":"kschuh","file_size":3108845,"file_name":"2021_NatureCommunications_Vandael.pdf","date_updated":"2021-12-17T11:34:50Z","success":1,"content_type":"application/pdf","checksum":"6036a8cdae95e1707c2a04d54e325ff4","file_id":"10563"}],"publisher":"Springer","abstract":[{"text":"The hippocampal mossy fiber synapse is a key synapse of the trisynaptic circuit. Post-tetanic potentiation (PTP) is the most powerful form of plasticity at this synaptic connection. It is widely believed that mossy fiber PTP is an entirely presynaptic phenomenon, implying that PTP induction is input-specific, and requires neither activity of multiple inputs nor stimulation of postsynaptic neurons. To directly test cooperativity and associativity, we made paired recordings between single mossy fiber terminals and postsynaptic CA3 pyramidal neurons in rat brain slices. By stimulating non-overlapping mossy fiber inputs converging onto single CA3 neurons, we confirm that PTP is input-specific and non-cooperative. Unexpectedly, mossy fiber PTP exhibits anti-associative induction properties. EPSCs show only minimal PTP after combined pre- and postsynaptic high-frequency stimulation with intact postsynaptic Ca2+ signaling, but marked PTP in the absence of postsynaptic spiking and after suppression of postsynaptic Ca2+ signaling (10 mM EGTA). PTP is largely recovered by inhibitors of voltage-gated R- and L-type Ca2+ channels, group II mGluRs, and vacuolar-type H+-ATPase, suggesting the involvement of retrograde vesicular glutamate signaling. Transsynaptic regulation of PTP extends the repertoire of synaptic computations, implementing a brake on mossy fiber detonation and a “smart teacher” function of hippocampal mossy fiber synapses.","lang":"eng"}],"quality_controlled":"1","title":"Transsynaptic modulation of presynaptic short-term plasticity in hippocampal mossy fiber synapses","publication_identifier":{"issn":["2041-1723"]}},{"status":"public","doi":"10.1038/s41467-021-25281-4","date_updated":"2023-08-11T11:07:51Z","oa":1,"article_type":"original","tmp":{"image":"/images/cc_by.png","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"file":[{"file_id":"9991","checksum":"1bf4f6a561f96bc426d754de9cb57710","content_type":"application/pdf","success":1,"date_updated":"2021-09-08T12:57:06Z","file_name":"2021_NatureCommunications_Watson.pdf","access_level":"open_access","creator":"cchlebak","file_size":18310502,"date_created":"2021-09-08T12:57:06Z","relation":"main_file"}],"publisher":"Nature Publishing Group","abstract":[{"lang":"eng","text":"AMPA receptor (AMPAR) abundance and positioning at excitatory synapses regulates the strength of transmission. Changes in AMPAR localisation can enact synaptic plasticity, allowing long-term information storage, and is therefore tightly controlled. Multiple mechanisms regulating AMPAR synaptic anchoring have been described, but with limited coherence or comparison between reports, our understanding of this process is unclear. Here, combining synaptic recordings from mouse hippocampal slices and super-resolution imaging in dissociated cultures, we compare the contributions of three AMPAR interaction domains controlling transmission at hippocampal CA1 synapses. We show that the AMPAR C-termini play only a modulatory role, whereas the extracellular N-terminal domain (NTD) and PDZ interactions of the auxiliary subunit TARP γ8 are both crucial, and each is sufficient to maintain transmission. Our data support a model in which γ8 accumulates AMPARs at the postsynaptic density, where the NTD further tunes their positioning. This interplay between cytosolic (TARP γ8) and synaptic cleft (NTD) interactions provides versatility to regulate synaptic transmission and plasticity."}],"title":"AMPA receptor anchoring at CA1 synapses is determined by N-terminal domain and TARP γ8 interactions","quality_controlled":"1","publication_identifier":{"eissn":["2041-1723"]},"article_processing_charge":"Yes","day":"23","publication":"Nature Communications","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","type":"journal_article","date_published":"2021-08-23T00:00:00Z","external_id":{"isi":["000687672000006"],"pmid":["34426577 "]},"_id":"9985","pmid":1,"date_created":"2021-09-05T22:01:23Z","file_date_updated":"2021-09-08T12:57:06Z","year":"2021","has_accepted_license":"1","issue":"1","article_number":"5083","citation":{"ista":"Watson J, Pinggera A, Ho H, Greger IH. 2021. AMPA receptor anchoring at CA1 synapses is determined by N-terminal domain and TARP γ8 interactions. Nature Communications. 12(1), 5083.","mla":"Watson, Jake, et al. “AMPA Receptor Anchoring at CA1 Synapses Is Determined by N-Terminal Domain and TARP Γ8 Interactions.” <i>Nature Communications</i>, vol. 12, no. 1, 5083, Nature Publishing Group, 2021, doi:<a href=\"https://doi.org/10.1038/s41467-021-25281-4\">10.1038/s41467-021-25281-4</a>.","ieee":"J. Watson, A. Pinggera, H. Ho, and I. H. Greger, “AMPA receptor anchoring at CA1 synapses is determined by N-terminal domain and TARP γ8 interactions,” <i>Nature Communications</i>, vol. 12, no. 1. Nature Publishing Group, 2021.","chicago":"Watson, Jake, Alexandra Pinggera, Hinze Ho, and Ingo H. Greger. “AMPA Receptor Anchoring at CA1 Synapses Is Determined by N-Terminal Domain and TARP Γ8 Interactions.” <i>Nature Communications</i>. Nature Publishing Group, 2021. <a href=\"https://doi.org/10.1038/s41467-021-25281-4\">https://doi.org/10.1038/s41467-021-25281-4</a>.","short":"J. Watson, A. Pinggera, H. Ho, I.H. Greger, Nature Communications 12 (2021).","apa":"Watson, J., Pinggera, A., Ho, H., &#38; Greger, I. H. (2021). AMPA receptor anchoring at CA1 synapses is determined by N-terminal domain and TARP γ8 interactions. <i>Nature Communications</i>. Nature Publishing Group. <a href=\"https://doi.org/10.1038/s41467-021-25281-4\">https://doi.org/10.1038/s41467-021-25281-4</a>","ama":"Watson J, Pinggera A, Ho H, Greger IH. AMPA receptor anchoring at CA1 synapses is determined by N-terminal domain and TARP γ8 interactions. <i>Nature Communications</i>. 2021;12(1). doi:<a href=\"https://doi.org/10.1038/s41467-021-25281-4\">10.1038/s41467-021-25281-4</a>"},"acknowledgement":"The authors are very grateful to Andrew Penn for advice and discussions on surface receptor labelling in slice tissue, dissociated culture transfection, and for providing tdTomato and BirAER expression plasmids. This work would not have been possible without support from the Biological Services teams at both the Laboratory of Molecular Biology and Ares facilities. We are also very grateful to Nick Barry and Jerome Boulanger of the LMB Light Microscopy facility for support with confocal and STORM imaging and analysis, Junichi Takagi for providing scFv-Clasp expression constructs, Veronica Chang for assistance with scFv-Clasp protein production, and Nejc Kejzar for assistance with cluster analysis. We would like to thank Teru Nakagawa and Ole Paulsen for critical reading of the manuscript and constructive feedback. This work was supported by grants from the Medical Research Council (MC_U105174197) and BBSRC (BB/N002113/1).","intvolume":"        12","ddc":["612"],"scopus_import":"1","month":"08","volume":12,"isi":1,"publication_status":"published","author":[{"id":"63836096-4690-11EA-BD4E-32803DDC885E","first_name":"Jake","last_name":"Watson","full_name":"Watson, Jake","orcid":"0000-0002-8698-3823"},{"first_name":"Alexandra","full_name":"Pinggera, Alexandra","last_name":"Pinggera"},{"first_name":"Hinze","full_name":"Ho, Hinze","last_name":"Ho"},{"first_name":"Ingo H.","full_name":"Greger, Ingo H.","last_name":"Greger"}],"department":[{"_id":"PeJo"}],"oa_version":"Published Version","language":[{"iso":"eng"}]},{"acknowledgement":"This project received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 692692 to P.J.) and the Fond zur Förderung der Wissenschaftlichen Forschung (Z 312-B27, Wittgenstein award to P.J., V 739-B27 to C.B.M.). We are grateful to F. Marr and C. Altmutter for excellent technical assistance and cell reconstruction, E. Kralli-Beller for manuscript editing, and the Scientific Service Units of IST Austria, especially T. Asenov and Miba machine shop, for maximally efficient support.","ddc":["570"],"intvolume":"        16","scopus_import":"1","month":"06","volume":16,"publication_status":"published","isi":1,"author":[{"full_name":"Vandael, David H","last_name":"Vandael","orcid":"0000-0001-7577-1676","id":"3AE48E0A-F248-11E8-B48F-1D18A9856A87","first_name":"David H"},{"last_name":"Okamoto","full_name":"Okamoto, Yuji","orcid":"0000-0003-0408-6094","id":"3337E116-F248-11E8-B48F-1D18A9856A87","first_name":"Yuji"},{"last_name":"Borges Merjane","full_name":"Borges Merjane, Carolina","orcid":"0000-0003-0005-401X","id":"4305C450-F248-11E8-B48F-1D18A9856A87","first_name":"Carolina"},{"first_name":"Victor M","id":"2F55A9DE-F248-11E8-B48F-1D18A9856A87","last_name":"Vargas Barroso","full_name":"Vargas Barroso, Victor M"},{"orcid":"0000-0002-9885-6936","full_name":"Suter, Benjamin","last_name":"Suter","first_name":"Benjamin","id":"4952F31E-F248-11E8-B48F-1D18A9856A87"},{"orcid":"0000-0001-5001-4804","last_name":"Jonas","full_name":"Jonas, Peter M","id":"353C1B58-F248-11E8-B48F-1D18A9856A87","first_name":"Peter M"}],"department":[{"_id":"PeJo"}],"page":"2947–2967","oa_version":"Submitted Version","language":[{"iso":"eng"}],"ec_funded":1,"has_accepted_license":"1","issue":"6","corr_author":"1","citation":{"short":"D.H. Vandael, Y. Okamoto, C. Borges Merjane, V.M. Vargas Barroso, B. Suter, P.M. Jonas, Nature Protocols 16 (2021) 2947–2967.","ama":"Vandael DH, Okamoto Y, Borges Merjane C, Vargas Barroso VM, Suter B, Jonas PM. Subcellular patch-clamp techniques for single-bouton stimulation and simultaneous pre- and postsynaptic recording at cortical synapses. <i>Nature Protocols</i>. 2021;16(6):2947–2967. doi:<a href=\"https://doi.org/10.1038/s41596-021-00526-0\">10.1038/s41596-021-00526-0</a>","apa":"Vandael, D. H., Okamoto, Y., Borges Merjane, C., Vargas Barroso, V. M., Suter, B., &#38; Jonas, P. M. (2021). Subcellular patch-clamp techniques for single-bouton stimulation and simultaneous pre- and postsynaptic recording at cortical synapses. <i>Nature Protocols</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41596-021-00526-0\">https://doi.org/10.1038/s41596-021-00526-0</a>","ista":"Vandael DH, Okamoto Y, Borges Merjane C, Vargas Barroso VM, Suter B, Jonas PM. 2021. Subcellular patch-clamp techniques for single-bouton stimulation and simultaneous pre- and postsynaptic recording at cortical synapses. Nature Protocols. 16(6), 2947–2967.","chicago":"Vandael, David H, Yuji Okamoto, Carolina Borges Merjane, Victor M Vargas Barroso, Benjamin Suter, and Peter M Jonas. “Subcellular Patch-Clamp Techniques for Single-Bouton Stimulation and Simultaneous Pre- and Postsynaptic Recording at Cortical Synapses.” <i>Nature Protocols</i>. Springer Nature, 2021. <a href=\"https://doi.org/10.1038/s41596-021-00526-0\">https://doi.org/10.1038/s41596-021-00526-0</a>.","ieee":"D. H. Vandael, Y. Okamoto, C. Borges Merjane, V. M. Vargas Barroso, B. Suter, and P. M. Jonas, “Subcellular patch-clamp techniques for single-bouton stimulation and simultaneous pre- and postsynaptic recording at cortical synapses,” <i>Nature Protocols</i>, vol. 16, no. 6. Springer Nature, pp. 2947–2967, 2021.","mla":"Vandael, David H., et al. “Subcellular Patch-Clamp Techniques for Single-Bouton Stimulation and Simultaneous Pre- and Postsynaptic Recording at Cortical Synapses.” <i>Nature Protocols</i>, vol. 16, no. 6, Springer Nature, 2021, pp. 2947–2967, doi:<a href=\"https://doi.org/10.1038/s41596-021-00526-0\">10.1038/s41596-021-00526-0</a>."},"article_processing_charge":"No","day":"01","publication":"Nature Protocols","type":"journal_article","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","date_published":"2021-06-01T00:00:00Z","acknowledged_ssus":[{"_id":"M-Shop"}],"_id":"9438","external_id":{"pmid":["33990799"],"isi":["000650528700003"]},"pmid":1,"date_created":"2021-05-30T22:01:24Z","file_date_updated":"2021-12-02T23:30:05Z","year":"2021","project":[{"_id":"25B7EB9E-B435-11E9-9278-68D0E5697425","grant_number":"692692","name":"Biophysics and circuit function of a giant cortical glutamatergic synapse","call_identifier":"H2020"},{"name":"Synaptic communication in neuronal microcircuits","grant_number":"Z00312","_id":"25C5A090-B435-11E9-9278-68D0E5697425","call_identifier":"FWF"},{"call_identifier":"FWF","name":"Structural plasticity at mossy fiber-CA3 synapses","grant_number":"V00739","_id":"2696E7FE-B435-11E9-9278-68D0E5697425"}],"status":"public","doi":"10.1038/s41596-021-00526-0","date_updated":"2025-04-22T22:30:43Z","oa":1,"article_type":"original","file":[{"date_updated":"2021-12-02T23:30:05Z","checksum":"7eb580abd8893cdb0b410cf41bc8c263","file_id":"9639","content_type":"application/pdf","access_level":"open_access","file_size":38574802,"creator":"cziletti","relation":"main_file","date_created":"2021-07-08T12:27:55Z","file_name":"VandaeletalAuthorVersion2021.pdf","embargo":"2021-12-01"}],"publisher":"Springer Nature","abstract":[{"lang":"eng","text":"Rigorous investigation of synaptic transmission requires analysis of unitary synaptic events by simultaneous recording from presynaptic terminals and postsynaptic target neurons. However, this has been achieved at only a limited number of model synapses, including the squid giant synapse and the mammalian calyx of Held. Cortical presynaptic terminals have been largely inaccessible to direct presynaptic recording, due to their small size. Here, we describe a protocol for improved subcellular patch-clamp recording in rat and mouse brain slices, with the synapse in a largely intact environment. Slice preparation takes ~2 h, recording ~3 h and post hoc morphological analysis 2 d. Single presynaptic hippocampal mossy fiber terminals are stimulated minimally invasively in the bouton-attached configuration, in which the cytoplasmic content remains unperturbed, or in the whole-bouton configuration, in which the cytoplasmic composition can be precisely controlled. Paired pre–postsynaptic recordings can be integrated with biocytin labeling and morphological analysis, allowing correlative investigation of synapse structure and function. Paired recordings can be obtained from mossy fiber terminals in slices from both rats and mice, implying applicability to genetically modified synapses. Paired recordings can also be performed together with axon tract stimulation or optogenetic activation, allowing comparison of unitary and compound synaptic events in the same target cell. Finally, paired recordings can be combined with spontaneous event analysis, permitting collection of miniature events generated at a single identified synapse. In conclusion, the subcellular patch-clamp techniques detailed here should facilitate analysis of biophysics, plasticity and circuit function of cortical synapses in the mammalian central nervous system."}],"title":"Subcellular patch-clamp techniques for single-bouton stimulation and simultaneous pre- and postsynaptic recording at cortical synapses","quality_controlled":"1","publication_identifier":{"issn":["1754-2189"],"eissn":["1750-2799"]}},{"publication":"eLife","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","type":"journal_article","article_processing_charge":"No","day":"29","file_date_updated":"2021-05-31T09:43:09Z","year":"2021","date_published":"2021-04-29T00:00:00Z","external_id":{"pmid":["33913808"],"isi":["000651761700001"]},"_id":"9437","date_created":"2021-05-30T22:01:23Z","pmid":1,"oa":1,"article_type":"original","tmp":{"image":"/images/cc_by.png","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"project":[{"call_identifier":"H2020","_id":"25CA28EA-B435-11E9-9278-68D0E5697425","name":"In situ analysis of single channel subunit composition in neurons: physiological implication in synaptic plasticity and behaviour","grant_number":"694539"},{"call_identifier":"H2020","_id":"25B7EB9E-B435-11E9-9278-68D0E5697425","grant_number":"692692","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"}],"date_updated":"2026-08-28T22:31:04Z","status":"public","doi":"10.7554/ELIFE.68274","publication_identifier":{"eissn":["2050-084X"]},"file":[{"date_updated":"2021-05-31T09:43:09Z","content_type":"application/pdf","file_id":"9440","checksum":"6ebcb79999f889766f7cd79ee134ad28","success":1,"file_size":8174719,"access_level":"open_access","creator":"cziletti","date_created":"2021-05-31T09:43:09Z","relation":"main_file","file_name":"2021_eLife_Bhandari.pdf"}],"publisher":"eLife Sciences Publications","quality_controlled":"1","abstract":[{"lang":"eng","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."}],"title":"GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals","volume":10,"month":"04","publication_status":"published","isi":1,"author":[{"id":"45EDD1BC-F248-11E8-B48F-1D18A9856A87","first_name":"Pradeep","orcid":"0000-0003-0863-4481","full_name":"Bhandari, Pradeep","last_name":"Bhandari"},{"id":"3AE48E0A-F248-11E8-B48F-1D18A9856A87","first_name":"David H","full_name":"Vandael, David H","last_name":"Vandael","orcid":"0000-0001-7577-1676"},{"last_name":"Fernández-Fernández","full_name":"Fernández-Fernández, Diego","first_name":"Diego"},{"full_name":"Fritzius, Thorsten","last_name":"Fritzius","first_name":"Thorsten"},{"id":"42E121A4-F248-11E8-B48F-1D18A9856A87","first_name":"David","full_name":"Kleindienst, David","last_name":"Kleindienst"},{"orcid":"0000-0002-2771-2011","full_name":"Önal, Hüseyin C","last_name":"Önal","id":"4659D740-F248-11E8-B48F-1D18A9856A87","first_name":"Hüseyin C"},{"full_name":"Montanaro-Punzengruber, Jacqueline-Claire","last_name":"Montanaro-Punzengruber","id":"3786AB44-F248-11E8-B48F-1D18A9856A87","first_name":"Jacqueline-Claire"},{"full_name":"Gassmann, Martin","last_name":"Gassmann","first_name":"Martin"},{"first_name":"Peter M","id":"353C1B58-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-5001-4804","full_name":"Jonas, Peter M","last_name":"Jonas"},{"last_name":"Kulik","full_name":"Kulik, Akos","first_name":"Akos"},{"full_name":"Bettler, Bernhard","last_name":"Bettler","first_name":"Bernhard"},{"first_name":"Ryuichi","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","full_name":"Shigemoto, Ryuichi","last_name":"Shigemoto","orcid":"0000-0001-8761-9444"},{"id":"3B8B25A8-F248-11E8-B48F-1D18A9856A87","first_name":"Peter","full_name":"Koppensteiner, Peter","last_name":"Koppensteiner","orcid":"0000-0002-3509-1948"}],"department":[{"_id":"RySh"},{"_id":"PeJo"}],"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.","intvolume":"        10","ddc":["570"],"scopus_import":"1","oa_version":"Published Version","language":[{"iso":"eng"}],"article_number":"e68274","citation":{"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>","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>","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.","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>."},"ec_funded":1,"related_material":{"link":[{"url":"https://doi.org/10.1101/2020.04.16.045112","relation":"earlier_version"}],"record":[{"relation":"dissertation_contains","id":"19271","status":"public"},{"relation":"dissertation_contains","id":"9562","status":"public"}]},"has_accepted_license":"1"},{"volume":1,"month":"12","department":[{"_id":"PeJo"}],"author":[{"id":"30CC5506-F248-11E8-B48F-1D18A9856A87","first_name":"José","orcid":"0000-0003-2209-5242","last_name":"Guzmán","full_name":"Guzmán, José"},{"id":"45BF87EE-F248-11E8-B48F-1D18A9856A87","first_name":"Alois","orcid":"0000-0002-5621-8100","full_name":"Schlögl, Alois","last_name":"Schlögl"},{"orcid":"0000-0003-4710-2082","last_name":"Espinoza Martinez","full_name":"Espinoza Martinez, Claudia ","first_name":"Claudia ","id":"31FFEE2E-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Xiaomin","id":"423EC9C2-F248-11E8-B48F-1D18A9856A87","full_name":"Zhang, Xiaomin","last_name":"Zhang","orcid":"0000-0003-0256-6529"},{"first_name":"Benjamin","id":"4952F31E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-9885-6936","last_name":"Suter","full_name":"Suter, Benjamin"},{"id":"353C1B58-F248-11E8-B48F-1D18A9856A87","first_name":"Peter M","full_name":"Jonas, Peter M","last_name":"Jonas","orcid":"0000-0001-5001-4804"}],"isi":1,"publication_status":"published","acknowledgement":"We thank A. Aertsen, N. Kopell, W. Maass, A. Roth, F. Stella and T. Vogels for critically reading earlier versions of the manuscript. We are grateful to F. Marr and C. Altmutter for excellent technical assistance, E. Kralli-Beller for manuscript editing, and the Scientific Service Units of IST Austria for efficient support. Finally, we thank T. Carnevale, L. Erdös, M. Hines, D. Nykamp and D. Schröder for useful discussions, and R. Friedrich and S. Wiechert for sharing unpublished data. This project received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 692692, P.J.) and the Fond zur Förderung der Wissenschaftlichen Forschung (Z 312-B27, Wittgenstein award to P.J. and P 31815 to S.J.G.).","scopus_import":"1","ddc":["610"],"intvolume":"         1","oa_version":"Submitted Version","page":"830-842","language":[{"iso":"eng"}],"OA_place":"repository","issue":"12","OA_type":"green","citation":{"ista":"Guzmán J, Schlögl A, Espinoza Martinez C, Zhang X, Suter B, Jonas PM. 2021. How connectivity rules and synaptic properties shape the efficacy of pattern separation in the entorhinal cortex–dentate gyrus–CA3 network. Nature Computational Science. 1(12), 830–842.","mla":"Guzmán, José, et al. “How Connectivity Rules and Synaptic Properties Shape the Efficacy of Pattern Separation in the Entorhinal Cortex–Dentate Gyrus–CA3 Network.” <i>Nature Computational Science</i>, vol. 1, no. 12, Springer Nature, 2021, pp. 830–42, doi:<a href=\"https://doi.org/10.1038/s43588-021-00157-1\">10.1038/s43588-021-00157-1</a>.","chicago":"Guzmán, José, Alois Schlögl, Claudia  Espinoza Martinez, Xiaomin Zhang, Benjamin Suter, and Peter M Jonas. “How Connectivity Rules and Synaptic Properties Shape the Efficacy of Pattern Separation in the Entorhinal Cortex–Dentate Gyrus–CA3 Network.” <i>Nature Computational Science</i>. Springer Nature, 2021. <a href=\"https://doi.org/10.1038/s43588-021-00157-1\">https://doi.org/10.1038/s43588-021-00157-1</a>.","ieee":"J. Guzmán, A. Schlögl, C. Espinoza Martinez, X. Zhang, B. Suter, and P. M. Jonas, “How connectivity rules and synaptic properties shape the efficacy of pattern separation in the entorhinal cortex–dentate gyrus–CA3 network,” <i>Nature Computational Science</i>, vol. 1, no. 12. Springer Nature, pp. 830–842, 2021.","short":"J. Guzmán, A. Schlögl, C. Espinoza Martinez, X. Zhang, B. Suter, P.M. Jonas, Nature Computational Science 1 (2021) 830–842.","apa":"Guzmán, J., Schlögl, A., Espinoza Martinez, C., Zhang, X., Suter, B., &#38; Jonas, P. M. (2021). How connectivity rules and synaptic properties shape the efficacy of pattern separation in the entorhinal cortex–dentate gyrus–CA3 network. <i>Nature Computational Science</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s43588-021-00157-1\">https://doi.org/10.1038/s43588-021-00157-1</a>","ama":"Guzmán J, Schlögl A, Espinoza Martinez C, Zhang X, Suter B, Jonas PM. How connectivity rules and synaptic properties shape the efficacy of pattern separation in the entorhinal cortex–dentate gyrus–CA3 network. <i>Nature Computational Science</i>. 2021;1(12):830-842. doi:<a href=\"https://doi.org/10.1038/s43588-021-00157-1\">10.1038/s43588-021-00157-1</a>"},"corr_author":"1","related_material":{"record":[{"id":"10110","status":"public","relation":"software"}],"link":[{"relation":"press_release","url":"https://ista.ac.at/en/news/spot-the-difference/","description":"News on ISTA Website"}]},"ec_funded":1,"has_accepted_license":"1","publication":"Nature Computational Science","type":"journal_article","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","day":"16","article_processing_charge":"No","biorxivid":1,"file_date_updated":"2022-06-18T22:30:03Z","year":"2021","acknowledged_ssus":[{"_id":"SSU"}],"_id":"10816","external_id":{"isi":["000888567500015"],"biorxivid":["10.1101/647800"]},"date_published":"2021-12-16T00:00:00Z","date_created":"2022-03-04T08:32:36Z","oa":1,"article_type":"original","status":"public","doi":"10.1038/s43588-021-00157-1","date_updated":"2026-07-28T12:15:17Z","project":[{"call_identifier":"H2020","name":"Biophysics and circuit function of a giant cortical glutamatergic synapse","grant_number":"692692","_id":"25B7EB9E-B435-11E9-9278-68D0E5697425"},{"_id":"25C5A090-B435-11E9-9278-68D0E5697425","name":"Synaptic communication in neuronal microcircuits","grant_number":"Z00312","call_identifier":"FWF"}],"publication_identifier":{"issn":["2662-8457"]},"file":[{"date_updated":"2022-06-18T22:30:03Z","checksum":"9fec5b667909ef52be96d502e4f8c2ae","file_id":"11430","content_type":"application/pdf","relation":"main_file","date_created":"2022-06-02T12:51:07Z","file_size":1699466,"access_level":"open_access","creator":"patrickd","embargo":"2022-06-17","file_name":"Guzmanetal2021.pdf"},{"relation":"supplementary_material","title":"Supplementary Material","date_created":"2022-06-02T12:53:47Z","file_size":3005651,"access_level":"open_access","creator":"patrickd","embargo":"2022-06-17","file_name":"Guzmanetal2021Suppl.pdf","date_updated":"2022-06-18T22:30:03Z","checksum":"52a005b13a114e3c3a28fa6bbe8b1a8d","content_type":"application/pdf","file_id":"11431"}],"quality_controlled":"1","title":"How connectivity rules and synaptic properties shape the efficacy of pattern separation in the entorhinal cortex–dentate gyrus–CA3 network","abstract":[{"text":"Pattern separation is a fundamental brain computation that converts small differences in input patterns into large differences in output patterns. Several synaptic mechanisms of pattern separation have been proposed, including code expansion, inhibition and plasticity; however, which of these mechanisms play a role in the entorhinal cortex (EC)–dentate gyrus (DG)–CA3 circuit, a classical pattern separation circuit, remains unclear. Here we show that a biologically realistic, full-scale EC–DG–CA3 circuit model, including granule cells (GCs) and parvalbumin-positive inhibitory interneurons (PV+-INs) in the DG, is an efficient pattern separator. Both external gamma-modulated inhibition and internal lateral inhibition mediated by PV+-INs substantially contributed to pattern separation. Both local connectivity and fast signaling at GC–PV+-IN synapses were important for maximum effectiveness. Similarly, mossy fiber synapses with conditional detonator properties contributed to pattern separation. By contrast, perforant path synapses with Hebbian synaptic plasticity and direct EC–CA3 connection shifted the network towards pattern completion. Our results demonstrate that the specific properties of cells and synapses optimize higher-order computations in biological networks and might be useful to improve the deep learning capabilities of technical networks.","lang":"eng"}],"publisher":"Springer Nature"},{"doi":"10.15479/AT:ISTA:10110","date_updated":"2026-08-28T22:31:05Z","status":"public","oa":1,"tmp":{"name":"GNU General Public License 3.0","legal_code_url":"https://www.gnu.org/licenses/gpl-3.0.en.html","short":"GPL 3.0"},"related_material":{"record":[{"status":"public","id":"10816","relation":"used_for_analysis_in"}],"link":[{"description":"News on IST Webpage","url":"https://ist.ac.at/en/news/spot-the-difference/","relation":"press_release"}]},"file":[{"checksum":"f92f8931cad0aa7e411c1715337bf408","content_type":"application/x-zip-compressed","file_id":"10114","success":1,"date_updated":"2021-10-08T08:46:04Z","file_name":"patternseparation-main (1).zip","creator":"cchlebak","access_level":"open_access","file_size":332990101,"relation":"main_file","date_created":"2021-10-08T08:46:04Z"}],"title":"How connectivity rules and synaptic properties shape the efficacy of pattern separation in the entorhinal cortex–dentate gyrus–CA3 network","abstract":[{"lang":"eng","text":"Pattern separation is a fundamental brain computation that converts small differences in input patterns into large differences in output patterns. Several synaptic mechanisms of pattern separation have been proposed, including code expansion, inhibition and plasticity; however, which of these mechanisms play a role in the entorhinal cortex (EC)–dentate gyrus (DG)–CA3 circuit, a classical pattern separation circuit, remains unclear. Here we show that a biologically realistic, full-scale EC–DG–CA3 circuit model, including granule cells (GCs) and parvalbumin-positive inhibitory interneurons (PV+-INs) in the DG, is an efficient pattern separator. Both external gamma-modulated inhibition and internal lateral inhibition mediated by PV+-INs substantially contributed to pattern separation. Both local connectivity and fast signaling at GC–PV+-IN synapses were important for maximum effectiveness. Similarly, mossy fiber synapses with conditional detonator properties contributed to pattern separation. By contrast, perforant path synapses with Hebbian synaptic plasticity and direct EC–CA3 connection shifted the network towards pattern completion. Our results demonstrate that the specific properties of cells and synapses optimize higher-order computations in biological networks and might be useful to improve the deep learning capabilities of technical networks."}],"publisher":"IST Austria","has_accepted_license":"1","citation":{"ama":"Guzmán J, Schlögl A, Espinoza Martinez C, Zhang X, Suter B, Jonas PM. How connectivity rules and synaptic properties shape the efficacy of pattern separation in the entorhinal cortex–dentate gyrus–CA3 network. 2021. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:10110\">10.15479/AT:ISTA:10110</a>","apa":"Guzmán, J., Schlögl, A., Espinoza Martinez, C., Zhang, X., Suter, B., &#38; Jonas, P. M. (2021). How connectivity rules and synaptic properties shape the efficacy of pattern separation in the entorhinal cortex–dentate gyrus–CA3 network. IST Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:10110\">https://doi.org/10.15479/AT:ISTA:10110</a>","short":"J. Guzmán, A. Schlögl, C. Espinoza Martinez, X. Zhang, B. Suter, P.M. Jonas, (2021).","ieee":"J. Guzmán, A. Schlögl, C. Espinoza Martinez, X. Zhang, B. Suter, and P. M. Jonas, “How connectivity rules and synaptic properties shape the efficacy of pattern separation in the entorhinal cortex–dentate gyrus–CA3 network.” IST Austria, 2021.","chicago":"Guzmán, José, Alois Schlögl, Claudia  Espinoza Martinez, Xiaomin Zhang, Benjamin Suter, and Peter M Jonas. “How Connectivity Rules and Synaptic Properties Shape the Efficacy of Pattern Separation in the Entorhinal Cortex–Dentate Gyrus–CA3 Network.” IST Austria, 2021. <a href=\"https://doi.org/10.15479/AT:ISTA:10110\">https://doi.org/10.15479/AT:ISTA:10110</a>.","mla":"Guzmán, José, et al. <i>How Connectivity Rules and Synaptic Properties Shape the Efficacy of Pattern Separation in the Entorhinal Cortex–Dentate Gyrus–CA3 Network</i>. IST Austria, 2021, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:10110\">10.15479/AT:ISTA:10110</a>.","ista":"Guzmán J, Schlögl A, Espinoza Martinez C, Zhang X, Suter B, Jonas PM. 2021. How connectivity rules and synaptic properties shape the efficacy of pattern separation in the entorhinal cortex–dentate gyrus–CA3 network, IST Austria, <a href=\"https://doi.org/10.15479/AT:ISTA:10110\">10.15479/AT:ISTA:10110</a>."},"day":"16","ddc":["005"],"month":"12","department":[{"_id":"PeJo"},{"_id":"ScienComp"}],"author":[{"full_name":"Guzmán, José","last_name":"Guzmán","orcid":"0000-0003-2209-5242","id":"30CC5506-F248-11E8-B48F-1D18A9856A87","first_name":"José"},{"id":"45BF87EE-F248-11E8-B48F-1D18A9856A87","first_name":"Alois","orcid":"0000-0002-5621-8100","last_name":"Schlögl","full_name":"Schlögl, Alois"},{"orcid":"0000-0003-4710-2082","full_name":"Espinoza Martinez, Claudia ","last_name":"Espinoza Martinez","first_name":"Claudia ","id":"31FFEE2E-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Xiaomin","id":"423EC9C2-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-0256-6529","last_name":"Zhang","full_name":"Zhang, Xiaomin"},{"orcid":"0000-0002-9885-6936","full_name":"Suter, Benjamin","last_name":"Suter","first_name":"Benjamin","id":"4952F31E-F248-11E8-B48F-1D18A9856A87"},{"orcid":"0000-0001-5001-4804","last_name":"Jonas","full_name":"Jonas, Peter M","id":"353C1B58-F248-11E8-B48F-1D18A9856A87","first_name":"Peter M"}],"user_id":"8b945eb4-e2f2-11eb-945a-df72226e66a9","type":"software","_id":"10110","date_published":"2021-12-16T00:00:00Z","license":"https://opensource.org/licenses/GPL-3.0","date_created":"2021-10-08T06:44:22Z","file_date_updated":"2021-10-08T08:46:04Z","year":"2021"},{"_id":"8001","acknowledged_ssus":[{"_id":"SSU"}],"external_id":{"isi":["000556135600004"],"pmid":["32492366"]},"date_published":"2020-08-05T00:00:00Z","pmid":1,"date_created":"2020-06-22T13:29:05Z","file_date_updated":"2020-11-25T11:23:02Z","year":"2020","day":"05","article_processing_charge":"No","publication":"Neuron","type":"journal_article","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","file":[{"date_updated":"2020-11-25T11:23:02Z","success":1,"file_id":"8811","checksum":"4030b2be0c9625d54694a1e9fb00305e","content_type":"application/pdf","relation":"main_file","date_created":"2020-11-25T11:23:02Z","file_size":4390833,"creator":"dernst","access_level":"open_access","file_name":"2020_Neuron_Vandael.pdf"}],"quality_controlled":"1","abstract":[{"text":"Post-tetanic potentiation (PTP) is an attractive candidate mechanism for hippocampus-dependent short-term memory. Although PTP has a uniquely large magnitude at hippocampal mossy fiber-CA3 pyramidal neuron synapses, it is unclear whether it can be induced by natural activity and whether its lifetime is sufficient to support short-term memory. We combined in vivo recordings from granule cells (GCs), in vitro paired recordings from mossy fiber terminals and postsynaptic CA3 neurons, and “flash and freeze” electron microscopy. PTP was induced at single synapses and showed a low induction threshold adapted to sparse GC activity in vivo. PTP was mainly generated by enlargement of the readily releasable pool of synaptic vesicles, allowing multiplicative interaction with other plasticity forms. PTP was associated with an increase in the docked vesicle pool, suggesting formation of structural “pool engrams.” Absence of presynaptic activity extended the lifetime of the potentiation, enabling prolonged information storage in the hippocampal network.","lang":"eng"}],"title":"Short-term plasticity at hippocampal mossy fiber synapses is induced by natural activity patterns and associated with vesicle pool engram formation","publisher":"Elsevier","publication_identifier":{"eissn":["10974199"],"issn":["0896-6273"]},"date_updated":"2025-04-15T08:29:09Z","status":"public","doi":"10.1016/j.neuron.2020.05.013","project":[{"call_identifier":"H2020","_id":"25B7EB9E-B435-11E9-9278-68D0E5697425","name":"Biophysics and circuit function of a giant cortical glutamatergic synapse","grant_number":"692692"},{"call_identifier":"FWF","_id":"25C5A090-B435-11E9-9278-68D0E5697425","grant_number":"Z00312","name":"Synaptic communication in neuronal microcircuits"},{"call_identifier":"FWF","grant_number":"V00739","name":"Structural plasticity at mossy fiber-CA3 synapses","_id":"2696E7FE-B435-11E9-9278-68D0E5697425"}],"oa":1,"article_type":"original","tmp":{"short":"CC BY-NC-ND (4.0)","image":"/images/cc_by_nc_nd.png","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode"},"oa_version":"Published Version","page":"509-521","language":[{"iso":"eng"}],"acknowledgement":"This project received funding from the European Research Council (ERC) under the European Union Horizon 2020 Research and Innovation Program (grant agreement 692692 to P.J.) and the Fond zur Förderung der Wissenschaftlichen Forschung ( Z 312-B27 , Wittgenstein award to P.J. and V 739-B27 to C.B.-M.). We thank Drs. Jozsef Csicsvari, Jose Guzman, Erwin Neher, and Ryuichi Shigemoto for commenting on earlier versions of the manuscript. We are grateful to Walter Kaufmann, Daniel Gütl, and Vanessa Zheden for EM training; Alois Schlögl for programming; Florian Marr for excellent technical assistance and cell reconstruction; Christina Altmutter for technical help; Eleftheria Kralli-Beller for manuscript editing; Taija Makinen for providing the Prox1-CreERT2 mouse line; and the Scientific Service Units of IST Austria for support.","scopus_import":"1","ddc":["570"],"intvolume":"       107","volume":107,"month":"08","department":[{"_id":"PeJo"}],"author":[{"first_name":"David H","id":"3AE48E0A-F248-11E8-B48F-1D18A9856A87","full_name":"Vandael, David H","last_name":"Vandael","orcid":"0000-0001-7577-1676"},{"first_name":"Carolina","id":"4305C450-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-0005-401X","last_name":"Borges Merjane","full_name":"Borges Merjane, Carolina"},{"last_name":"Zhang","full_name":"Zhang, Xiaomin","id":"423EC9C2-F248-11E8-B48F-1D18A9856A87","first_name":"Xiaomin"},{"orcid":"0000-0001-5001-4804","full_name":"Jonas, Peter M","last_name":"Jonas","id":"353C1B58-F248-11E8-B48F-1D18A9856A87","first_name":"Peter M"}],"isi":1,"publication_status":"published","related_material":{"link":[{"url":"https://ist.ac.at/en/news/possible-physical-trace-of-short-term-memory-found/","description":"News on IST Homepage","relation":"press_release"}]},"ec_funded":1,"has_accepted_license":"1","issue":"3","citation":{"short":"D.H. Vandael, C. Borges Merjane, X. Zhang, P.M. Jonas, Neuron 107 (2020) 509–521.","ama":"Vandael DH, Borges Merjane C, Zhang X, Jonas PM. Short-term plasticity at hippocampal mossy fiber synapses is induced by natural activity patterns and associated with vesicle pool engram formation. <i>Neuron</i>. 2020;107(3):509-521. doi:<a href=\"https://doi.org/10.1016/j.neuron.2020.05.013\">10.1016/j.neuron.2020.05.013</a>","apa":"Vandael, D. H., Borges Merjane, C., Zhang, X., &#38; Jonas, P. M. (2020). Short-term plasticity at hippocampal mossy fiber synapses is induced by natural activity patterns and associated with vesicle pool engram formation. <i>Neuron</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.neuron.2020.05.013\">https://doi.org/10.1016/j.neuron.2020.05.013</a>","ista":"Vandael DH, Borges Merjane C, Zhang X, Jonas PM. 2020. Short-term plasticity at hippocampal mossy fiber synapses is induced by natural activity patterns and associated with vesicle pool engram formation. Neuron. 107(3), 509–521.","ieee":"D. H. Vandael, C. Borges Merjane, X. Zhang, and P. M. Jonas, “Short-term plasticity at hippocampal mossy fiber synapses is induced by natural activity patterns and associated with vesicle pool engram formation,” <i>Neuron</i>, vol. 107, no. 3. Elsevier, pp. 509–521, 2020.","chicago":"Vandael, David H, Carolina Borges Merjane, Xiaomin Zhang, and Peter M Jonas. “Short-Term Plasticity at Hippocampal Mossy Fiber Synapses Is Induced by Natural Activity Patterns and Associated with Vesicle Pool Engram Formation.” <i>Neuron</i>. Elsevier, 2020. <a href=\"https://doi.org/10.1016/j.neuron.2020.05.013\">https://doi.org/10.1016/j.neuron.2020.05.013</a>.","mla":"Vandael, David H., et al. “Short-Term Plasticity at Hippocampal Mossy Fiber Synapses Is Induced by Natural Activity Patterns and Associated with Vesicle Pool Engram Formation.” <i>Neuron</i>, vol. 107, no. 3, Elsevier, 2020, pp. 509–21, doi:<a href=\"https://doi.org/10.1016/j.neuron.2020.05.013\">10.1016/j.neuron.2020.05.013</a>."},"corr_author":"1"},{"related_material":{"link":[{"url":"https://ist.ac.at/en/news/the-bouncer-in-the-brain/","description":"News on IST Website","relation":"press_release"}]},"ec_funded":1,"has_accepted_license":"1","issue":"6","citation":{"apa":"Zhang, X., Schlögl, A., &#38; Jonas, P. M. (2020). Selective routing of spatial information flow from input to output in hippocampal granule cells. <i>Neuron</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.neuron.2020.07.006\">https://doi.org/10.1016/j.neuron.2020.07.006</a>","ama":"Zhang X, Schlögl A, Jonas PM. Selective routing of spatial information flow from input to output in hippocampal granule cells. <i>Neuron</i>. 2020;107(6):1212-1225. doi:<a href=\"https://doi.org/10.1016/j.neuron.2020.07.006\">10.1016/j.neuron.2020.07.006</a>","short":"X. Zhang, A. Schlögl, P.M. Jonas, Neuron 107 (2020) 1212–1225.","mla":"Zhang, Xiaomin, et al. “Selective Routing of Spatial Information Flow from Input to Output in Hippocampal Granule Cells.” <i>Neuron</i>, vol. 107, no. 6, Elsevier, 2020, pp. 1212–25, doi:<a href=\"https://doi.org/10.1016/j.neuron.2020.07.006\">10.1016/j.neuron.2020.07.006</a>.","ieee":"X. Zhang, A. Schlögl, and P. M. Jonas, “Selective routing of spatial information flow from input to output in hippocampal granule cells,” <i>Neuron</i>, vol. 107, no. 6. Elsevier, pp. 1212–1225, 2020.","chicago":"Zhang, Xiaomin, Alois Schlögl, and Peter M Jonas. “Selective Routing of Spatial Information Flow from Input to Output in Hippocampal Granule Cells.” <i>Neuron</i>. Elsevier, 2020. <a href=\"https://doi.org/10.1016/j.neuron.2020.07.006\">https://doi.org/10.1016/j.neuron.2020.07.006</a>.","ista":"Zhang X, Schlögl A, Jonas PM. 2020. Selective routing of spatial information flow from input to output in hippocampal granule cells. Neuron. 107(6), 1212–1225."},"corr_author":"1","acknowledgement":"This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement 692692, P.J.) and the Fond zur Förderung der Wissenschaftlichen Forschung (Z 312-B27, Wittgenstein award, P.J.). We thank Gyorgy Buzsáki, Jozsef Csicsvari, Juan Ramirez Villegas, and Federico Stella for commenting on earlier versions of this manuscript. We also thank Katie Bittner, Michael Brecht, Albert Lee, Jeffery Magee, and Alejandro Pernía-Andrade for sharing expertise in in vivo patch-clamp recording. We are grateful to Florian Marr for cell labeling, cell reconstruction, and technical assistance; Ben Suter for helpful discussions; Christina Altmutter for technical support; Eleftheria Kralli-Beller for manuscript editing; and Todor Asenov (Machine Shop) for device construction. We also thank the Scientific Service Units (SSUs) of IST Austria (Machine Shop, Scientific Computing, and Preclinical Facility) for efficient support.","scopus_import":"1","ddc":["570"],"intvolume":"       107","volume":107,"month":"09","department":[{"_id":"PeJo"},{"_id":"ScienComp"}],"author":[{"id":"423EC9C2-F248-11E8-B48F-1D18A9856A87","first_name":"Xiaomin","full_name":"Zhang, Xiaomin","last_name":"Zhang"},{"orcid":"0000-0002-5621-8100","last_name":"Schlögl","full_name":"Schlögl, Alois","first_name":"Alois","id":"45BF87EE-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Jonas","full_name":"Jonas, Peter M","orcid":"0000-0001-5001-4804","first_name":"Peter M","id":"353C1B58-F248-11E8-B48F-1D18A9856A87"}],"isi":1,"publication_status":"published","oa_version":"Published Version","page":"1212-1225","language":[{"iso":"eng"}],"status":"public","doi":"10.1016/j.neuron.2020.07.006","date_updated":"2025-04-15T08:29:03Z","project":[{"call_identifier":"H2020","_id":"25B7EB9E-B435-11E9-9278-68D0E5697425","name":"Biophysics and circuit function of a giant cortical glutamatergic synapse","grant_number":"692692"},{"_id":"25C5A090-B435-11E9-9278-68D0E5697425","grant_number":"Z00312","name":"Synaptic communication in neuronal microcircuits","call_identifier":"FWF"}],"oa":1,"tmp":{"short":"CC BY-NC-ND (4.0)","image":"/images/cc_by_nc_nd.png","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode"},"article_type":"original","file":[{"date_updated":"2020-12-04T09:29:21Z","file_id":"8920","content_type":"application/pdf","checksum":"44a5960fc083a4cb3488d22224859fdc","success":1,"file_size":3011120,"creator":"dernst","access_level":"open_access","date_created":"2020-12-04T09:29:21Z","relation":"main_file","file_name":"2020_Neuron_Zhang.pdf"}],"quality_controlled":"1","title":"Selective routing of spatial information flow from input to output in hippocampal granule cells","abstract":[{"lang":"eng","text":"Dentate gyrus granule cells (GCs) connect the entorhinal cortex to the hippocampal CA3 region, but how they process spatial information remains enigmatic. To examine the role of GCs in spatial coding, we measured excitatory postsynaptic potentials (EPSPs) and action potentials (APs) in head-fixed mice running on a linear belt. Intracellular recording from morphologically identified GCs revealed that most cells were active, but activity level varied over a wide range. Whereas only ∼5% of GCs showed spatially tuned spiking, ∼50% received spatially tuned input. Thus, the GC population broadly encodes spatial information, but only a subset relays this information to the CA3 network. Fourier analysis indicated that GCs received conjunctive place-grid-like synaptic input, suggesting code conversion in single neurons. GC firing was correlated with dendritic complexity and intrinsic excitability, but not extrinsic excitatory input or dendritic cable properties. Thus, functional maturation may control input-output transformation and spatial code conversion."}],"publisher":"Elsevier","publication_identifier":{"issn":["0896-6273"]},"day":"23","article_processing_charge":"No","publication":"Neuron","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","type":"journal_article","external_id":{"isi":["000579698700009"],"pmid":["32763145"]},"_id":"8261","acknowledged_ssus":[{"_id":"M-Shop"},{"_id":"ScienComp"},{"_id":"PreCl"}],"date_published":"2020-09-23T00:00:00Z","pmid":1,"date_created":"2020-08-14T09:36:05Z","file_date_updated":"2020-12-04T09:29:21Z","year":"2020"},{"has_accepted_license":"1","ec_funded":1,"related_material":{"link":[{"url":"https://ist.ac.at/en/news/flash-and-freeze-reveals-dynamics-of-nerve-connections/","description":"News on IST Homepage","relation":"press_release"}],"record":[{"relation":"dissertation_contains","status":"public","id":"11196"}]},"corr_author":"1","citation":{"short":"C. Borges Merjane, O. Kim, P.M. Jonas, Neuron 105 (2020) 992–1006.","apa":"Borges Merjane, C., Kim, O., &#38; Jonas, P. M. (2020). Functional electron microscopy (“Flash and Freeze”) of identified cortical synapses in acute brain slices. <i>Neuron</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.neuron.2019.12.022\">https://doi.org/10.1016/j.neuron.2019.12.022</a>","ama":"Borges Merjane C, Kim O, Jonas PM. Functional electron microscopy (“Flash and Freeze”) of identified cortical synapses in acute brain slices. <i>Neuron</i>. 2020;105:992-1006. doi:<a href=\"https://doi.org/10.1016/j.neuron.2019.12.022\">10.1016/j.neuron.2019.12.022</a>","ista":"Borges Merjane C, Kim O, Jonas PM. 2020. Functional electron microscopy (“Flash and Freeze”) of identified cortical synapses in acute brain slices. Neuron. 105, 992–1006.","mla":"Borges Merjane, Carolina, et al. “Functional Electron Microscopy (‘Flash and Freeze’) of Identified Cortical Synapses in Acute Brain Slices.” <i>Neuron</i>, vol. 105, Elsevier, 2020, pp. 992–1006, doi:<a href=\"https://doi.org/10.1016/j.neuron.2019.12.022\">10.1016/j.neuron.2019.12.022</a>.","ieee":"C. Borges Merjane, O. Kim, and P. M. Jonas, “Functional electron microscopy (‘Flash and Freeze’) of identified cortical synapses in acute brain slices,” <i>Neuron</i>, vol. 105. Elsevier, pp. 992–1006, 2020.","chicago":"Borges Merjane, Carolina, Olena Kim, and Peter M Jonas. “Functional Electron Microscopy (‘Flash and Freeze’) of Identified Cortical Synapses in Acute Brain Slices.” <i>Neuron</i>. Elsevier, 2020. <a href=\"https://doi.org/10.1016/j.neuron.2019.12.022\">https://doi.org/10.1016/j.neuron.2019.12.022</a>."},"language":[{"iso":"eng"}],"page":"992-1006","oa_version":"Published Version","intvolume":"       105","ddc":["570"],"scopus_import":"1","acknowledgement":"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. 692692 and Marie Sklodowska-Curie 708497) and from Fonds zur Förderung der Wissenschaftlichen Forschung (Z 312-B27 Wittgenstein award and DK W1205-B09). We thank Johann Danzl and Ryuichi Shigemoto for critically reading the manuscript; Walter Kaufmann, Daniel Gutl, and Vanessa Zheden for extensive EM training, advice, and experimental assistance; Benjamin Suter for substantial help with light stimulation, ImageJ plugins for analysis, and manuscript editing; Florian Marr and Christina Altmutter for technical support; Eleftheria Kralli-Beller for manuscript editing; Julia König and Paul Wurzinger (Leica Microsystems) for helpful technical discussions; and Taija Makinen for providing the Prox1-CreERT2 mouse line.","publication_status":"published","isi":1,"department":[{"_id":"PeJo"}],"author":[{"full_name":"Borges Merjane, Carolina","last_name":"Borges Merjane","orcid":"0000-0003-0005-401X","id":"4305C450-F248-11E8-B48F-1D18A9856A87","first_name":"Carolina"},{"orcid":"0000-0003-2344-1039","last_name":"Kim","full_name":"Kim, Olena","first_name":"Olena","id":"3F8ABDDA-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Jonas, Peter M","last_name":"Jonas","orcid":"0000-0001-5001-4804","id":"353C1B58-F248-11E8-B48F-1D18A9856A87","first_name":"Peter M"}],"month":"03","volume":105,"publisher":"Elsevier","title":"Functional electron microscopy (“Flash and Freeze”) of identified cortical synapses in acute brain slices","abstract":[{"lang":"eng","text":"How structural and functional properties of synapses relate to each other is a fundamental question in neuroscience. Electrophysiology has elucidated mechanisms of synaptic transmission, and electron microscopy (EM) has provided insight into morphological properties of synapses. Here we describe an enhanced method for functional EM (“flash and freeze”), combining optogenetic stimulation with high-pressure freezing. We demonstrate that the improved method can be applied to intact networks in acute brain slices and organotypic slice cultures from mice. As a proof of concept, we probed vesicle pool changes during synaptic transmission at the hippocampal mossy fiber-CA3 pyramidal neuron synapse. Our findings show overlap of the docked vesicle pool and the functionally defined readily releasable pool and provide evidence of fast endocytosis at this synapse. Functional EM with acute slices and slice cultures has the potential to reveal the structural and functional mechanisms of transmission in intact, genetically perturbed, and disease-affected synapses."}],"quality_controlled":"1","file":[{"success":1,"file_id":"8778","content_type":"application/pdf","checksum":"3582664addf26859e86ac5bec3e01416","date_updated":"2020-11-20T08:58:53Z","file_name":"2020_Neuron_BorgesMerjane.pdf","relation":"main_file","date_created":"2020-11-20T08:58:53Z","creator":"dernst","file_size":9712957,"access_level":"open_access"}],"publication_identifier":{"issn":["0896-6273"]},"project":[{"_id":"25B7EB9E-B435-11E9-9278-68D0E5697425","name":"Biophysics and circuit function of a giant cortical glutamatergic synapse","grant_number":"692692","call_identifier":"H2020"},{"call_identifier":"H2020","_id":"25BAF7B2-B435-11E9-9278-68D0E5697425","name":"Presynaptic calcium channels distribution and impact on coupling at the hippocampal mossy fiber synapse","grant_number":"708497"},{"_id":"25C5A090-B435-11E9-9278-68D0E5697425","name":"Synaptic communication in neuronal microcircuits","grant_number":"Z00312","call_identifier":"FWF"},{"call_identifier":"FWF","grant_number":"W01205","name":"Zellkommunikation in Gesundheit und Krankheit","_id":"25C3DBB6-B435-11E9-9278-68D0E5697425"}],"status":"public","date_updated":"2026-08-28T22:30:04Z","doi":"10.1016/j.neuron.2019.12.022","article_type":"original","tmp":{"short":"CC BY-NC-ND (4.0)","image":"/images/cc_by_nc_nd.png","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode"},"oa":1,"date_created":"2020-02-10T15:59:45Z","pmid":1,"date_published":"2020-03-18T00:00:00Z","_id":"7473","external_id":{"isi":["000520854700008"],"pmid":["31928842"]},"year":"2020","file_date_updated":"2020-11-20T08:58:53Z","article_processing_charge":"No","day":"18","type":"journal_article","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","publication":"Neuron"},{"status":"public","date_updated":"2025-09-23T11:44:57Z","doi":"10.1007/978-3-662-56468-4_7","series_title":"Springer-Lehrbuch","OA_type":"closed access","corr_author":"1","citation":{"ista":"Jonas PM. 2019.Aktionspotenzial: Fortleitung im Axon. In: Physiologie des Menschen. , 72–82.","mla":"Jonas, Peter M. “Aktionspotenzial: Fortleitung im Axon.” <i>Physiologie des Menschen</i>, 32nd ed., Springer Nature, 2019, pp. 72–82, doi:<a href=\"https://doi.org/10.1007/978-3-662-56468-4_7\">10.1007/978-3-662-56468-4_7</a>.","chicago":"Jonas, Peter M. “Aktionspotenzial: Fortleitung im Axon.” In <i>Physiologie des Menschen</i>, 32nd ed., 72–82. Springer-Lehrbuch. Berlin, Heidelberg: Springer Nature, 2019. <a href=\"https://doi.org/10.1007/978-3-662-56468-4_7\">https://doi.org/10.1007/978-3-662-56468-4_7</a>.","ieee":"P. M. Jonas, “Aktionspotenzial: Fortleitung im Axon,” in <i>Physiologie des Menschen</i>, 32nd ed., Berlin, Heidelberg: Springer Nature, 2019, pp. 72–82.","short":"P.M. Jonas, in:, Physiologie des Menschen, 32nd ed., Springer Nature, Berlin, Heidelberg, 2019, pp. 72–82.","apa":"Jonas, P. M. (2019). Aktionspotenzial: Fortleitung im Axon. In <i>Physiologie des Menschen</i> (32nd ed., pp. 72–82). Berlin, Heidelberg: Springer Nature. <a href=\"https://doi.org/10.1007/978-3-662-56468-4_7\">https://doi.org/10.1007/978-3-662-56468-4_7</a>","ama":"Jonas PM. Aktionspotenzial: Fortleitung im Axon. In: <i>Physiologie des Menschen</i>. 32nd ed. Springer-Lehrbuch. Berlin, Heidelberg: Springer Nature; 2019:72-82. doi:<a href=\"https://doi.org/10.1007/978-3-662-56468-4_7\">10.1007/978-3-662-56468-4_7</a>"},"publication_identifier":{"issn":["0937-7433"],"isbn":["9783662564677"],"eissn":["2512-5214"],"eisbn":["9783662564684"]},"publisher":"Springer Nature","quality_controlled":"1","title":"Aktionspotenzial: Fortleitung im Axon","abstract":[{"text":"Neurone empfangen Eingangssignale, konvertieren diese in Aktionspotenziale und generieren schließlich Ausgangssignale auf ihren Zielzellen. Dabei sind die zu überwindenden räumlichen Distanzen oft groß. Daher ist entscheidend, dass elektrische Signale in Nervenzellen schnell von einem zum anderen Ort geleitet werden können. Diese wichtige Aufgabe erfüllt das Axon, der „Ausgangsfortsatz“ der Nervenzelle. Für die schnelle Leitung des Aktionspotenzials sind sowohl die passiven Eigenschaften des axonalen Kabels als auch die aktiven Eigenschaften der Zellmembran von entscheidender Bedeutung. Die Evolution bedient sich zweier Tricks, um die Leitungsgeschwindigkeit des Aktionspotenzials zu maximieren. Der eine Trick ist die Zunahme des Axondurchmessers. Der andere Trick ist die Ausbildung von Markscheiden. Dies führt bei nahezu gleichem Platzbedarf zu einer Zunahme der Leistungsgeschwindigkeit um fast zwei Größenordnungen. Die Aktionspotenzialleitung an myelinisierten Axonen erfolgt „saltatorisch“.","lang":"ger"}],"month":"04","publication":"Physiologie des Menschen","publication_status":"published","type":"book_chapter","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","author":[{"id":"353C1B58-F248-11E8-B48F-1D18A9856A87","first_name":"Peter M","last_name":"Jonas","full_name":"Jonas, Peter M","orcid":"0000-0001-5001-4804"}],"department":[{"_id":"PeJo"}],"place":"Berlin, Heidelberg","article_processing_charge":"No","day":"02","page":"72-82","oa_version":"None","year":"2019","language":[{"iso":"ger"}],"date_published":"2019-04-02T00:00:00Z","_id":"19989","edition":"32","date_created":"2025-07-10T13:36:36Z"},{"publication":"eLife","type":"journal_article","user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","article_processing_charge":"No","day":"31","file_date_updated":"2020-07-14T12:47:57Z","year":"2019","date_published":"2019-05-31T00:00:00Z","_id":"7405","external_id":{"pmid":["31025934"],"isi":["000468968400001"]},"pmid":1,"date_created":"2020-01-30T09:08:01Z","oa":1,"tmp":{"image":"/images/cc_by.png","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"article_type":"original","date_updated":"2023-09-07T14:27:52Z","doi":"10.7554/elife.44494","status":"public","publication_identifier":{"issn":["2050-084X"]},"file":[{"creator":"dernst","file_size":6182359,"access_level":"open_access","relation":"main_file","date_created":"2020-02-04T08:41:47Z","file_name":"2019_eLife_DuraBernal.pdf","date_updated":"2020-07-14T12:47:57Z","file_id":"7444","content_type":"application/pdf","checksum":"7014189c11c10a12feeeae37f054871d"}],"publisher":"eLife Sciences Publications","abstract":[{"lang":"eng","text":"Biophysical modeling of neuronal networks helps to integrate and interpret rapidly growing and disparate experimental datasets at multiple scales. The NetPyNE tool (www.netpyne.org) provides both programmatic and graphical interfaces to develop data-driven multiscale network models in NEURON. NetPyNE clearly separates model parameters from implementation code. Users provide specifications at a high level via a standardized declarative language, for example connectivity rules, to create millions of cell-to-cell connections. NetPyNE then enables users to generate the NEURON network, run efficiently parallelized simulations, optimize and explore network parameters through automated batch runs, and use built-in functions for visualization and analysis – connectivity matrices, voltage traces, spike raster plots, local field potentials, and information theoretic measures. NetPyNE also facilitates model sharing by exporting and importing standardized formats (NeuroML and SONATA). NetPyNE is already being used to teach computational neuroscience students and by modelers to investigate brain regions and phenomena."}],"title":"NetPyNE, a tool for data-driven multiscale modeling of brain circuits","quality_controlled":"1","volume":8,"month":"05","publication_status":"published","isi":1,"department":[{"_id":"PeJo"}],"author":[{"first_name":"Salvador","full_name":"Dura-Bernal, Salvador","last_name":"Dura-Bernal"},{"first_name":"Benjamin","id":"4952F31E-F248-11E8-B48F-1D18A9856A87","last_name":"Suter","full_name":"Suter, Benjamin","orcid":"0000-0002-9885-6936"},{"last_name":"Gleeson","full_name":"Gleeson, Padraig","first_name":"Padraig"},{"first_name":"Matteo","last_name":"Cantarelli","full_name":"Cantarelli, Matteo"},{"first_name":"Adrian","full_name":"Quintana, Adrian","last_name":"Quintana"},{"first_name":"Facundo","last_name":"Rodriguez","full_name":"Rodriguez, Facundo"},{"last_name":"Kedziora","full_name":"Kedziora, David J","first_name":"David J"},{"first_name":"George L","last_name":"Chadderdon","full_name":"Chadderdon, George L"},{"last_name":"Kerr","full_name":"Kerr, Cliff C","first_name":"Cliff C"},{"first_name":"Samuel A","full_name":"Neymotin, Samuel A","last_name":"Neymotin"},{"full_name":"McDougal, Robert A","last_name":"McDougal","first_name":"Robert A"},{"full_name":"Hines, Michael","last_name":"Hines","first_name":"Michael"},{"last_name":"Shepherd","full_name":"Shepherd, Gordon MG","first_name":"Gordon MG"},{"first_name":"William W","last_name":"Lytton","full_name":"Lytton, William W"}],"intvolume":"         8","ddc":["570"],"scopus_import":"1","oa_version":"Published Version","language":[{"iso":"eng"}],"article_number":"e44494","citation":{"apa":"Dura-Bernal, S., Suter, B., Gleeson, P., Cantarelli, M., Quintana, A., Rodriguez, F., … Lytton, W. W. (2019). NetPyNE, a tool for data-driven multiscale modeling of brain circuits. <i>ELife</i>. eLife Sciences Publications. <a href=\"https://doi.org/10.7554/elife.44494\">https://doi.org/10.7554/elife.44494</a>","ama":"Dura-Bernal S, Suter B, Gleeson P, et al. NetPyNE, a tool for data-driven multiscale modeling of brain circuits. <i>eLife</i>. 2019;8. doi:<a href=\"https://doi.org/10.7554/elife.44494\">10.7554/elife.44494</a>","short":"S. Dura-Bernal, B. Suter, P. Gleeson, M. Cantarelli, A. Quintana, F. Rodriguez, D.J. Kedziora, G.L. Chadderdon, C.C. Kerr, S.A. Neymotin, R.A. McDougal, M. Hines, G.M. Shepherd, W.W. Lytton, ELife 8 (2019).","mla":"Dura-Bernal, Salvador, et al. “NetPyNE, a Tool for Data-Driven Multiscale Modeling of Brain Circuits.” <i>ELife</i>, vol. 8, e44494, eLife Sciences Publications, 2019, doi:<a href=\"https://doi.org/10.7554/elife.44494\">10.7554/elife.44494</a>.","ieee":"S. Dura-Bernal <i>et al.</i>, “NetPyNE, a tool for data-driven multiscale modeling of brain circuits,” <i>eLife</i>, vol. 8. eLife Sciences Publications, 2019.","chicago":"Dura-Bernal, Salvador, Benjamin Suter, Padraig Gleeson, Matteo Cantarelli, Adrian Quintana, Facundo Rodriguez, David J Kedziora, et al. “NetPyNE, a Tool for Data-Driven Multiscale Modeling of Brain Circuits.” <i>ELife</i>. eLife Sciences Publications, 2019. <a href=\"https://doi.org/10.7554/elife.44494\">https://doi.org/10.7554/elife.44494</a>.","ista":"Dura-Bernal S, Suter B, Gleeson P, Cantarelli M, Quintana A, Rodriguez F, Kedziora DJ, Chadderdon GL, Kerr CC, Neymotin SA, McDougal RA, Hines M, Shepherd GM, Lytton WW. 2019. NetPyNE, a tool for data-driven multiscale modeling of brain circuits. eLife. 8, e44494."},"has_accepted_license":"1"},{"publication_status":"published","conference":{"location":"Innsbruck, Austria","start_date":"2019-09-25","end_date":"2019-09-27","name":"ANA: Austrian Neuroscience Association ; APHAR: Austrian Pharmacological Society"},"author":[{"first_name":"Olena","id":"3F8ABDDA-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-2344-1039","full_name":"Kim, Olena","last_name":"Kim"},{"orcid":"0000-0003-0005-401X","full_name":"Borges Merjane, Carolina","last_name":"Borges Merjane","id":"4305C450-F248-11E8-B48F-1D18A9856A87","first_name":"Carolina"},{"id":"353C1B58-F248-11E8-B48F-1D18A9856A87","first_name":"Peter M","full_name":"Jonas, Peter M","last_name":"Jonas","orcid":"0000-0001-5001-4804"}],"department":[{"_id":"PeJo"}],"volume":7,"month":"09","ddc":["570"],"intvolume":"         7","acknowledgement":"This work was supported by the ERC and EU Horizon 2020 (ERC 692692; MSC-IF 708497) and FWF Z 312-B27 Wittgenstein award; W 1205-B09).","language":[{"iso":"eng"}],"oa_version":"Published Version","corr_author":"1","article_number":"A3.27","citation":{"ieee":"O. Kim, C. Borges Merjane, and P. M. Jonas, “Functional analysis of the docked vesicle pool in hippocampal mossy fiber terminals by electron microscopy,” in <i>Intrinsic Activity</i>, Innsbruck, Austria, 2019, vol. 7, no. Suppl. 1.","chicago":"Kim, Olena, Carolina Borges Merjane, and Peter M Jonas. “Functional Analysis of the Docked Vesicle Pool in Hippocampal Mossy Fiber Terminals by Electron Microscopy.” In <i>Intrinsic Activity</i>, Vol. 7. Austrian Pharmacological Society, 2019. <a href=\"https://doi.org/10.25006/ia.7.s1-a3.27\">https://doi.org/10.25006/ia.7.s1-a3.27</a>.","mla":"Kim, Olena, et al. “Functional Analysis of the Docked Vesicle Pool in Hippocampal Mossy Fiber Terminals by Electron Microscopy.” <i>Intrinsic Activity</i>, vol. 7, no. Suppl. 1, A3.27, Austrian Pharmacological Society, 2019, doi:<a href=\"https://doi.org/10.25006/ia.7.s1-a3.27\">10.25006/ia.7.s1-a3.27</a>.","ista":"Kim O, Borges Merjane C, Jonas PM. 2019. Functional analysis of the docked vesicle pool in hippocampal mossy fiber terminals by electron microscopy. Intrinsic Activity. ANA: Austrian Neuroscience Association ; APHAR: Austrian Pharmacological Society vol. 7, A3.27.","ama":"Kim O, Borges Merjane C, Jonas PM. Functional analysis of the docked vesicle pool in hippocampal mossy fiber terminals by electron microscopy. In: <i>Intrinsic Activity</i>. Vol 7. Austrian Pharmacological Society; 2019. doi:<a href=\"https://doi.org/10.25006/ia.7.s1-a3.27\">10.25006/ia.7.s1-a3.27</a>","apa":"Kim, O., Borges Merjane, C., &#38; Jonas, P. M. (2019). Functional analysis of the docked vesicle pool in hippocampal mossy fiber terminals by electron microscopy. In <i>Intrinsic Activity</i> (Vol. 7). Innsbruck, Austria: Austrian Pharmacological Society. <a href=\"https://doi.org/10.25006/ia.7.s1-a3.27\">https://doi.org/10.25006/ia.7.s1-a3.27</a>","short":"O. Kim, C. Borges Merjane, P.M. Jonas, in:, Intrinsic Activity, Austrian Pharmacological Society, 2019."},"issue":"Suppl. 1","ec_funded":1,"related_material":{"record":[{"status":"public","id":"11196","relation":"dissertation_contains"}]},"type":"conference_abstract","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publication":"Intrinsic Activity","article_processing_charge":"No","day":"11","year":"2019","date_created":"2022-04-20T15:06:05Z","date_published":"2019-09-11T00:00:00Z","_id":"11222","oa":1,"project":[{"_id":"25B7EB9E-B435-11E9-9278-68D0E5697425","name":"Biophysics and circuit function of a giant cortical glutamatergic synapse","grant_number":"692692","call_identifier":"H2020"},{"call_identifier":"H2020","_id":"25BAF7B2-B435-11E9-9278-68D0E5697425","name":"Presynaptic calcium channels distribution and impact on coupling at the hippocampal mossy fiber synapse","grant_number":"708497"},{"name":"Zellkommunikation in Gesundheit und Krankheit","grant_number":"W01205","_id":"25C3DBB6-B435-11E9-9278-68D0E5697425","call_identifier":"FWF"},{"call_identifier":"FWF","grant_number":"Z00312","name":"Synaptic communication in neuronal microcircuits","_id":"25C5A090-B435-11E9-9278-68D0E5697425"}],"keyword":["hippocampus","mossy fibers","readily releasable pool","electron microscopy"],"doi":"10.25006/ia.7.s1-a3.27","date_updated":"2026-08-28T22:30:04Z","status":"public","publication_identifier":{"issn":["2309-8503"]},"main_file_link":[{"open_access":"1","url":"https://www.intrinsicactivity.org/2019/7/S1/A3.27/"}],"publisher":"Austrian Pharmacological Society","title":"Functional analysis of the docked vesicle pool in hippocampal mossy fiber terminals by electron microscopy","quality_controlled":"1"},{"citation":{"apa":"Espinoza Martinez, C. (2019). <i>Parvalbumin+ interneurons enable efficient pattern separation in hippocampal microcircuits</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:6363\">https://doi.org/10.15479/AT:ISTA:6363</a>","ama":"Espinoza Martinez C. Parvalbumin+ interneurons enable efficient pattern separation in hippocampal microcircuits. 2019. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:6363\">10.15479/AT:ISTA:6363</a>","short":"C. Espinoza Martinez, Parvalbumin+ Interneurons Enable Efficient Pattern Separation in Hippocampal Microcircuits, Institute of Science and Technology Austria, 2019.","mla":"Espinoza Martinez, Claudia. <i>Parvalbumin+ Interneurons Enable Efficient Pattern Separation in Hippocampal Microcircuits</i>. Institute of Science and Technology Austria, 2019, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:6363\">10.15479/AT:ISTA:6363</a>.","chicago":"Espinoza Martinez, Claudia . “Parvalbumin+ Interneurons Enable Efficient Pattern Separation in Hippocampal Microcircuits.” Institute of Science and Technology Austria, 2019. <a href=\"https://doi.org/10.15479/AT:ISTA:6363\">https://doi.org/10.15479/AT:ISTA:6363</a>.","ieee":"C. Espinoza Martinez, “Parvalbumin+ interneurons enable efficient pattern separation in hippocampal microcircuits,” Institute of Science and Technology Austria, 2019.","ista":"Espinoza Martinez C. 2019. Parvalbumin+ interneurons enable efficient pattern separation in hippocampal microcircuits. Institute of Science and Technology Austria."},"corr_author":"1","related_material":{"record":[{"relation":"part_of_dissertation","id":"21","status":"public"}]},"degree_awarded":"PhD","alternative_title":["ISTA Thesis"],"has_accepted_license":"1","OA_place":"publisher","supervisor":[{"id":"353C1B58-F248-11E8-B48F-1D18A9856A87","first_name":"Peter M","last_name":"Jonas","full_name":"Jonas, Peter M","orcid":"0000-0001-5001-4804"}],"oa_version":"Published Version","page":"140","language":[{"iso":"eng"}],"month":"04","author":[{"last_name":"Espinoza Martinez","full_name":"Espinoza Martinez, Claudia ","orcid":"0000-0003-4710-2082","id":"31FFEE2E-F248-11E8-B48F-1D18A9856A87","first_name":"Claudia "}],"department":[{"_id":"PeJo"}],"publication_status":"published","ddc":["570"],"publication_identifier":{"issn":["2663-337X"],"isbn":["978-3-99078-000-8"]},"file":[{"file_size":13966891,"creator":"cespinoza","access_level":"open_access","date_created":"2019-05-07T16:00:39Z","relation":"main_file","embargo":"2020-05-09","file_name":"Espinozathesis_all2.pdf","date_updated":"2021-02-11T11:17:15Z","file_id":"6389","content_type":"application/pdf","checksum":"77c6c05cfe8b58c8abcf1b854375d084"},{"relation":"source_file","embargo_to":"open_access","date_created":"2019-05-07T16:00:48Z","creator":"cespinoza","access_level":"closed","file_size":11159900,"file_name":"Espinoza_Thesis.docx","date_updated":"2020-07-14T12:47:28Z","checksum":"f6aa819f127691a2b0fc21c76eb09746","file_id":"6390","content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document"}],"abstract":[{"lang":"eng","text":"Distinguishing  between  similar  experiences  is  achieved  by  the  brain  in  a  process called  pattern  separation.  In  the  hippocampus,  pattern  separation  reduces  the interference of memories and increases the storage capacity by decorrelating similar inputs  patterns  of  neuronal  activity  into  non-overlapping output  firing  patterns. Winners-take-all  (WTA)  mechanism  is  a  theoretical  model  for  pattern  separation  in which  a  \"winner\"  cell  suppresses  the  activity  of  the  neighboring  neurons  through feedback inhibition. However, if the network properties of the dentate gyrus support WTA as a biologically conceivable model remains unknown. Here, we showed that the connectivity rules of PV+interneurons and their synaptic properties are optimizedfor efficient pattern separation. We found using multiple whole-cell in vitrorecordings that PV+interneurons mainly connect to granule cells (GC) through lateral inhibition, a form of  feedback  inhibition  in  which  a  GC  inhibits  other  GCs  but  not  itself  through  the activation of PV+interneurons. Thus, lateral inhibition between GC–PV+interneurons was ~10 times more abundant than recurrent connections. Furthermore, the GC–PV+interneuron  connectivity  was  more  spatially  confined  but  less  abundant  than  PV+interneurons–GC  connectivity,  leading  to  an  asymmetrical  distribution  of  excitatory and inhibitory connectivity. Our network model of the dentate gyrus with incorporated real connectivity rules efficiently decorrelates neuronal activity patterns using WTA as the  primary  mechanism.  This  process  relied  on  lateral  inhibition,  fast-signaling properties  of  PV+interneurons  and  the  asymmetrical  distribution  of  excitatory  and inhibitory connectivity. Finally, we found that silencing the activity of PV+interneurons in  vivoleads  to  acute  deficits  in  discrimination  between  similar  environments, suggesting  that  PV+interneuron  networks  are  necessary  for  behavioral  relevant computations.  Our   results   demonstrate   that   PV+interneurons  possess  unique connectivity  and  fast  signaling  properties  that confer  to  the  dentate  gyrus  network properties that allow the emergence of pattern separation. Thus, our results contribute to the knowledge of how specific forms of network organization underlie sophisticated types of information processing. \r\n"}],"title":"Parvalbumin+ interneurons enable efficient pattern separation in hippocampal microcircuits","publisher":"Institute of Science and Technology Austria","oa":1,"date_updated":"2026-04-08T13:57:19Z","status":"public","doi":"10.15479/AT:ISTA:6363","file_date_updated":"2021-02-11T11:17:15Z","year":"2019","_id":"6363","date_published":"2019-04-30T00:00:00Z","date_created":"2019-04-30T11:56:10Z","type":"dissertation","user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","day":"30","article_processing_charge":"No"},{"department":[{"_id":"PeJo"}],"author":[{"last_name":"Hu","full_name":"Hu, Hua","first_name":"Hua","id":"4AC0145C-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Fabian","full_name":"Roth, Fabian","last_name":"Roth"},{"orcid":"0000-0001-7577-1676","full_name":"Vandael, David H","last_name":"Vandael","first_name":"David H","id":"3AE48E0A-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Peter M","id":"353C1B58-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-5001-4804","last_name":"Jonas","full_name":"Jonas, Peter M"}],"isi":1,"publication_status":"published","month":"04","volume":98,"scopus_import":"1","intvolume":"        98","ddc":["570"],"language":[{"iso":"eng"}],"oa_version":"Published Version","page":"156 - 165","citation":{"apa":"Hu, H., Roth, F., Vandael, D. H., &#38; Jonas, P. M. (2018). Complementary tuning of Na+ and K+ channel gating underlies fast and energy-efficient action potentials in GABAergic interneuron axons. <i>Neuron</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.neuron.2018.02.024\">https://doi.org/10.1016/j.neuron.2018.02.024</a>","ama":"Hu H, Roth F, Vandael DH, Jonas PM. Complementary tuning of Na+ and K+ channel gating underlies fast and energy-efficient action potentials in GABAergic interneuron axons. <i>Neuron</i>. 2018;98(1):156-165. doi:<a href=\"https://doi.org/10.1016/j.neuron.2018.02.024\">10.1016/j.neuron.2018.02.024</a>","short":"H. Hu, F. Roth, D.H. Vandael, P.M. Jonas, Neuron 98 (2018) 156–165.","mla":"Hu, Hua, et al. “Complementary Tuning of Na+ and K+ Channel Gating Underlies Fast and Energy-Efficient Action Potentials in GABAergic Interneuron Axons.” <i>Neuron</i>, vol. 98, no. 1, Elsevier, 2018, pp. 156–65, doi:<a href=\"https://doi.org/10.1016/j.neuron.2018.02.024\">10.1016/j.neuron.2018.02.024</a>.","chicago":"Hu, Hua, Fabian Roth, David H Vandael, and Peter M Jonas. “Complementary Tuning of Na+ and K+ Channel Gating Underlies Fast and Energy-Efficient Action Potentials in GABAergic Interneuron Axons.” <i>Neuron</i>. Elsevier, 2018. <a href=\"https://doi.org/10.1016/j.neuron.2018.02.024\">https://doi.org/10.1016/j.neuron.2018.02.024</a>.","ieee":"H. Hu, F. Roth, D. H. Vandael, and P. M. Jonas, “Complementary tuning of Na+ and K+ channel gating underlies fast and energy-efficient action potentials in GABAergic interneuron axons,” <i>Neuron</i>, vol. 98, no. 1. Elsevier, pp. 156–165, 2018.","ista":"Hu H, Roth F, Vandael DH, Jonas PM. 2018. Complementary tuning of Na+ and K+ channel gating underlies fast and energy-efficient action potentials in GABAergic interneuron axons. Neuron. 98(1), 156–165."},"corr_author":"1","issue":"1","has_accepted_license":"1","related_material":{"link":[{"relation":"press_release","url":"https://ist.ac.at/en/news/a-certain-type-of-neurons-is-more-energy-efficient-than-previously-assumed/","description":"News on IST Homepage"}]},"ec_funded":1,"user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","type":"journal_article","publication":"Neuron","day":"04","article_processing_charge":"Yes (in subscription journal)","publist_id":"7545","year":"2018","file_date_updated":"2020-07-14T12:46:03Z","date_created":"2018-12-11T11:45:48Z","_id":"320","external_id":{"isi":["000429192100016"]},"date_published":"2018-04-04T00:00:00Z","tmp":{"image":"/images/cc_by.png","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"oa":1,"doi":"10.1016/j.neuron.2018.02.024","status":"public","date_updated":"2025-04-15T08:29:04Z","project":[{"call_identifier":"FP7","_id":"25C0F108-B435-11E9-9278-68D0E5697425","name":"Nanophysiology of fast-spiking, parvalbumin-expressing GABAergic interneurons","grant_number":"268548"},{"_id":"25B7EB9E-B435-11E9-9278-68D0E5697425","grant_number":"692692","name":"Biophysics and circuit function of a giant cortical glutamatergic synapse","call_identifier":"H2020"},{"call_identifier":"FWF","_id":"25C26B1E-B435-11E9-9278-68D0E5697425","grant_number":"P24909-B24","name":"Mechanisms of transmitter release at GABAergic synapses"},{"_id":"25C5A090-B435-11E9-9278-68D0E5697425","name":"Synaptic communication in neuronal microcircuits","grant_number":"Z00312","call_identifier":"FWF"}],"title":"Complementary tuning of Na+ and K+ channel gating underlies fast and energy-efficient action potentials in GABAergic interneuron axons","abstract":[{"lang":"eng","text":"Fast-spiking, parvalbumin-expressing GABAergic interneurons (PV+-BCs) express a complex machinery of rapid signaling mechanisms, including specialized voltage-gated ion channels to generate brief action potentials (APs). However, short APs are associated with overlapping Na+ and K+ fluxes and are therefore energetically expensive. How the potentially vicious combination of high AP frequency and inefficient spike generation can be reconciled with limited energy supply is presently unclear. To address this question, we performed direct recordings from the PV+-BC axon, the subcellular structure where active conductances for AP initiation and propagation are located. Surprisingly, the energy required for the AP was, on average, only ∼1.6 times the theoretical minimum. High energy efficiency emerged from the combination of fast inactivation of Na+ channels and delayed activation of Kv3-type K+ channels, which minimized ion flux overlap during APs. Thus, the complementary tuning of axonal Na+ and K+ channel gating optimizes both fast signaling properties and metabolic efficiency. Hu et al. demonstrate that action potentials in parvalbumin-expressing GABAergic interneuron axons are energetically efficient, which is highly unexpected given their brief duration. High energy efficiency emerges from the combination of fast inactivation of voltage-gated Na+ channels and delayed activation of Kv3 channels in the axon. "}],"quality_controlled":"1","publisher":"Elsevier","file":[{"content_type":"application/pdf","file_id":"5690","checksum":"76070f3729f9c603e1080d0151aa2b11","date_updated":"2020-07-14T12:46:03Z","file_name":"2018_Neuron_Hu.pdf","relation":"main_file","date_created":"2018-12-17T10:37:50Z","creator":"dernst","access_level":"open_access","file_size":3180444}]},{"abstract":[{"text":"Neuronal networks in the brain consist of two main types of neuron, glutamatergic principal neurons and GABAergic interneurons. Although these interneurons only represent 10–20% of the whole population, they mediate feedback and feedforward inhibition and are involved in the generation of high-frequency network oscillations. A hallmark functional property of GABAergic interneurons, especially of the parvalbumin‑expressing (PV+) subtypes, is the speed of signaling at their output synapse across species and brain regions. Several molecular and subcellular factors may underlie the submillisecond signaling at GABAergic synapses. Such as the selective use of P/Q type Ca2+ channels and the tight coupling between Ca2+ channels and Ca2+ sensors of exocytosis. However, whether the molecular identity of the release sensor contributes to these signaling properties remains unclear. Besides, these interneurons are mainly show depression in response to train of stimuli. How could they keep sufficient release to control the activity of postsynaptic principal neurons during high network activity, is largely elusive. For my Ph.D. work, we firstly examined the Ca2+ sensor of exocytosis at the GABAergic basket cell (BC) to Purkinje cell (PC) synapse in the cerebellum. Immunolabeling suggested that BC terminals selectively expressed synaptotagmin 2 (Syt2), whereas synaptotagmin 1 (Syt1) was enriched in excitatory terminals. Genetic elimination of Syt2 reduced action potential-evoked release to ~10% compared to the wild-type control, identifying Syt2 as the major Ca2+ sensor at BC‑PC synapses. Differential adenovirus-mediated rescue revealed Syt2 triggered release with shorter latency and higher temporal precision, and mediated faster vesicle pool replenishment than Syt1. Furthermore, deletion of Syt2 severely reduced and delayed disynaptic inhibition following parallel fiber stimulation. Thus, the selective use of Syt2 as the release sensor at BC–PC synapse ensures fast feedforward inhibition in cerebellar microcircuits. Additionally, we tested the function of another synaptotagmin member, Syt7, for inhibitory synaptic transmission at the BC–PC synapse. Syt7 is thought to be a Ca2+ sensor that mediates asynchronous transmitter release and facilitation at synapses. However, it is strongly expressed in fast-spiking, PV+ GABAergic interneurons and the output synapses of these neurons produce only minimal asynchronous release and show depression rather than facilitation. How could Syt7, a facilitation sensor, contribute to the depressed inhibitory synaptic transmission needs to be further investigated and understood. Our results indicated that at the BC–PC synapse, Syt7 contributes to asynchronous release, pool replenishment and facilitation. In combination, these three effects ensure efficient transmitter release during high‑frequency activity and guarantee frequency independence of inhibition. Taken together, our results confirmed that Syt2, which has the fastest kinetic properties among all synaptotagmin members, is mainly used by the inhibitory BC‑PC synapse for synaptic transmission, contributing to the speed and temporal precision of transmitter release. Furthermore, we showed that Syt7, another highly expressed synaptotagmin member in the output synapses of cerebellar BCs, is used for ensuring efficient inhibitor synaptic transmission during high activity.","lang":"eng"}],"title":"Synaptotagmins ensure speed and efficiency of inhibitory neurotransmitter release","publisher":"Institute of Science and Technology Austria","file":[{"checksum":"8e163ae9e927401b9fa7c1b3e6a3631a","content_type":"application/pdf","file_id":"5046","date_updated":"2020-07-14T12:46:04Z","file_name":"IST-2018-997-v1+1_Thesis_chong_a.pdf","relation":"main_file","date_created":"2018-12-12T10:13:58Z","file_size":8719458,"access_level":"open_access","creator":"system"},{"relation":"source_file","date_created":"2019-04-05T09:25:26Z","file_size":47841940,"creator":"dernst","access_level":"closed","file_name":"2018_Thesis_chong_source.pages","date_updated":"2020-07-14T12:46:04Z","checksum":"f7d7260029a5fbb5c982db61328ade52","content_type":"application/octet-stream","file_id":"6221"}],"publication_identifier":{"issn":["2663-337X"]},"doi":"10.15479/AT:ISTA:th_997","date_updated":"2026-04-08T14:09:29Z","status":"public","tmp":{"image":"/images/cc_by.png","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"oa":1,"date_created":"2018-12-11T11:45:49Z","_id":"324","date_published":"2018-03-01T00:00:00Z","publist_id":"7541","year":"2018","file_date_updated":"2020-07-14T12:46:04Z","day":"01","article_processing_charge":"No","type":"dissertation","user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","has_accepted_license":"1","related_material":{"record":[{"relation":"part_of_dissertation","status":"public","id":"1117"},{"id":"749","status":"public","relation":"part_of_dissertation"}]},"degree_awarded":"PhD","alternative_title":["ISTA Thesis"],"citation":{"ista":"Chen C. 2018. Synaptotagmins ensure speed and efficiency of inhibitory neurotransmitter release. Institute of Science and Technology Austria.","mla":"Chen, Chong. <i>Synaptotagmins Ensure Speed and Efficiency of Inhibitory Neurotransmitter Release</i>. Institute of Science and Technology Austria, 2018, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:th_997\">10.15479/AT:ISTA:th_997</a>.","chicago":"Chen, Chong. “Synaptotagmins Ensure Speed and Efficiency of Inhibitory Neurotransmitter Release.” Institute of Science and Technology Austria, 2018. <a href=\"https://doi.org/10.15479/AT:ISTA:th_997\">https://doi.org/10.15479/AT:ISTA:th_997</a>.","ieee":"C. Chen, “Synaptotagmins ensure speed and efficiency of inhibitory neurotransmitter release,” Institute of Science and Technology Austria, 2018.","short":"C. Chen, Synaptotagmins Ensure Speed and Efficiency of Inhibitory Neurotransmitter Release, Institute of Science and Technology Austria, 2018.","apa":"Chen, C. (2018). <i>Synaptotagmins ensure speed and efficiency of inhibitory neurotransmitter release</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:th_997\">https://doi.org/10.15479/AT:ISTA:th_997</a>","ama":"Chen C. Synaptotagmins ensure speed and efficiency of inhibitory neurotransmitter release. 2018. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:th_997\">10.15479/AT:ISTA:th_997</a>"},"corr_author":"1","supervisor":[{"last_name":"Jonas","full_name":"Jonas, Peter M","orcid":"0000-0001-5001-4804","id":"353C1B58-F248-11E8-B48F-1D18A9856A87","first_name":"Peter M"}],"OA_place":"publisher","pubrep_id":"997","language":[{"iso":"eng"}],"oa_version":"Published Version","page":"110","ddc":["571"],"department":[{"_id":"PeJo"}],"author":[{"id":"3DFD581A-F248-11E8-B48F-1D18A9856A87","first_name":"Chong","full_name":"Chen, Chong","last_name":"Chen"}],"publication_status":"published","month":"03"}]