[{"date_updated":"2026-04-07T12:40:42Z","oa_version":"Published Version","publication_status":"published","license":"https://creativecommons.org/licenses/by-nc/4.0/","project":[{"grant_number":"694539","name":"In situ analysis of single channel subunit composition in neurons: physiological implication in synaptic plasticity and behaviour","call_identifier":"H2020","_id":"25CA28EA-B435-11E9-9278-68D0E5697425"},{"grant_number":"665385","name":"International IST Doctoral Program","_id":"2564DBCA-B435-11E9-9278-68D0E5697425","call_identifier":"H2020"}],"year":"2025","supervisor":[{"orcid":"0000-0001-8761-9444","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","last_name":"Shigemoto","first_name":"Ryuichi","full_name":"Shigemoto, Ryuichi"}],"corr_author":"1","degree_awarded":"PhD","date_created":"2025-02-28T14:15:53Z","oa":1,"abstract":[{"lang":"eng","text":"The medial habenula (MHb) is implicated in regulating emotional responses\r\nto aversive events. Studies in zebrafish have identified a remarkable morphological\r\nleft-right asymmetry in the dorsal habenula (zebrafish equivalent of mammalian\r\nMHb)-to-interpeduncular nucleus (IPN) pathway and its left-side specific role in\r\nmodulating fear responses. However, there is little evidence for structural or\r\nfunctional lateralization in the mammalian MHb-IPN pathway.\r\nHere, I investigated the synaptic properties of the left and right MHb\r\nafferents to the IPN in mice and addressed whether these synaptic connections\r\nselectively influence the expression of conditioned fear in mice. My findings reveal\r\nthat each individual IPN neuron receives inputs from both left and right MHb.\r\nElectrophysiological recordings from the same postsynaptic IPN neurons\r\ndemonstrate that the left MHb-originating synapses exhibit lower release\r\nprobability and higher 𝛾-aminobutyric acid type B receptor (GABABR)-mediated\r\npotentiation compared to the right MHb-originating synapses. Interestingly,\r\nchemogenetic inhibition of cholinergic neurons in the left but not the right MHb\r\nsignificantly attenuated cue-dependent fear recall. Furthermore, conditional\r\ndeletion of GABABR in the left MHb interfered with the recall of cued fear memory,\r\nwhereas that in the right MHb neurons spared fear memory expression.\r\nCollectively, I demonstrate a functional asymmetry of the MHb in mice,\r\nrevealing a predominant role for GABABR-mediated signaling in the left MHb-IPN\r\npathway in the modulation of fear memories. These findings suggest that\r\nlateralized pathways could represent a fundamental principle in the neural\r\nregulation of emotion across species."}],"title":"Asymmetrical modulation of fear expression via GABAB receptors in the mouse medial habenula","_id":"19271","status":"public","ddc":["570","571","573","599"],"language":[{"iso":"eng"}],"user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","tmp":{"name":"Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)","short":"CC BY-NC (4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc/4.0/legalcode","image":"/images/cc_by_nc.png"},"acknowledged_ssus":[{"_id":"PreCl"},{"_id":"M-Shop"}],"OA_place":"publisher","author":[{"last_name":"Önal","first_name":"Hüseyin C","full_name":"Önal, Hüseyin C","orcid":"0000-0002-2771-2011","id":"4659D740-F248-11E8-B48F-1D18A9856A87"}],"ec_funded":1,"department":[{"_id":"GradSch"},{"_id":"RySh"}],"related_material":{"record":[{"id":"9437","relation":"part_of_dissertation","status":"public"},{"relation":"part_of_dissertation","status":"public","id":"15084"}]},"acknowledgement":"I would like to thank the European Research Council and European Commission, under the European Union’s Horizon 2020 research and innovation program (ERC grant agreement no. 694539 to Ryuichi Shigemoto and the Marie Skłodowska-Curie grant agreement no. 665385 to Cihan Önal), and the Austrian Neuroscience Association for providing financial support and opportunities, which were important in allowing me to present my work. I also wish to thank the\r\nPreclinical Facility, especially Michael Schunn, for always welcoming me from my earliest days as an intern. My gratitude goes as well to the Miba Machine Shop, in particular Todor Asenov, Astrit Arslani, and Thomas Menner, whose technical expertise often saved the day.","file_date_updated":"2026-02-01T23:30:02Z","article_processing_charge":"No","date_published":"2025-03-04T00:00:00Z","day":"04","citation":{"mla":"Önal, Cihan. <i>Asymmetrical Modulation of Fear Expression via GABAB Receptors in the Mouse Medial Habenula</i>. Institute of Science and Technology Austria, 2025, doi:<a href=\"https://doi.org/10.15479/AT-ISTA-19271\">10.15479/AT-ISTA-19271</a>.","apa":"Önal, C. (2025). <i>Asymmetrical modulation of fear expression via GABAB receptors in the mouse medial habenula</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT-ISTA-19271\">https://doi.org/10.15479/AT-ISTA-19271</a>","short":"C. Önal, Asymmetrical Modulation of Fear Expression via GABAB Receptors in the Mouse Medial Habenula, Institute of Science and Technology Austria, 2025.","ama":"Önal C. Asymmetrical modulation of fear expression via GABAB receptors in the mouse medial habenula. 2025. doi:<a href=\"https://doi.org/10.15479/AT-ISTA-19271\">10.15479/AT-ISTA-19271</a>","chicago":"Önal, Cihan. “Asymmetrical Modulation of Fear Expression via GABAB Receptors in the Mouse Medial Habenula.” Institute of Science and Technology Austria, 2025. <a href=\"https://doi.org/10.15479/AT-ISTA-19271\">https://doi.org/10.15479/AT-ISTA-19271</a>.","ista":"Önal C. 2025. Asymmetrical modulation of fear expression via GABAB receptors in the mouse medial habenula. Institute of Science and Technology Austria.","ieee":"C. Önal, “Asymmetrical modulation of fear expression via GABAB receptors in the mouse medial habenula,” Institute of Science and Technology Austria, 2025."},"publisher":"Institute of Science and Technology Austria","file":[{"creator":"hoenal","file_name":"Cihan_Onal_Thesis_Final.docx","file_id":"19272","date_created":"2025-02-28T13:57:01Z","relation":"source_file","checksum":"c1a4d75a7471de9f954697b06cd18d28","embargo_to":"open_access","date_updated":"2026-02-01T23:30:02Z","content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document","access_level":"closed","file_size":25869143},{"date_updated":"2026-02-01T23:30:02Z","content_type":"application/pdf","access_level":"open_access","file_size":12077596,"checksum":"de4e62147ab9f04098dc8cd898c630da","relation":"main_file","date_created":"2025-02-28T13:57:04Z","embargo":"2026-02-01","file_id":"19273","file_name":"Cihan_Onal_Thesis_Final_pdfa.pdf","creator":"hoenal"}],"has_accepted_license":"1","doi":"10.15479/AT-ISTA-19271","type":"dissertation","month":"03","alternative_title":["ISTA Thesis"],"publication_identifier":{"eissn":["2663-337X"]}},{"OA_place":"publisher","acknowledged_ssus":[{"_id":"M-Shop"},{"_id":"PreCl"},{"_id":"EM-Fac"}],"ec_funded":1,"author":[{"id":"3B8B25A8-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-3509-1948","full_name":"Koppensteiner, Peter","last_name":"Koppensteiner","first_name":"Peter"},{"id":"45EDD1BC-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-0863-4481","full_name":"Bhandari, Pradeep","first_name":"Pradeep","last_name":"Bhandari"},{"orcid":"0000-0002-2771-2011","id":"4659D740-F248-11E8-B48F-1D18A9856A87","first_name":"Hüseyin C","last_name":"Önal","full_name":"Önal, Hüseyin C"},{"full_name":"Borges Merjane, Carolina","first_name":"Carolina","last_name":"Borges Merjane","id":"4305C450-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-0005-401X"},{"id":"3B59276A-F248-11E8-B48F-1D18A9856A87","full_name":"Le Monnier, Elodie","last_name":"Le Monnier","first_name":"Elodie"},{"full_name":"Roy, Utsa","last_name":"Roy","first_name":"Utsa","id":"4d26cf11-5355-11ee-ae5a-eb05e255b9b2"},{"full_name":"Nakamura, Yukihiro","last_name":"Nakamura","first_name":"Yukihiro"},{"last_name":"Sadakata","first_name":"Tetsushi","full_name":"Sadakata, Tetsushi"},{"first_name":"Makoto","last_name":"Sanbo","full_name":"Sanbo, Makoto"},{"full_name":"Hirabayashi, Masumi","last_name":"Hirabayashi","first_name":"Masumi"},{"full_name":"Rhee, JeongSeop","first_name":"JeongSeop","last_name":"Rhee"},{"last_name":"Brose","first_name":"Nils","full_name":"Brose, Nils"},{"last_name":"Jonas","first_name":"Peter M","full_name":"Jonas, Peter M","orcid":"0000-0001-5001-4804","id":"353C1B58-F248-11E8-B48F-1D18A9856A87"},{"orcid":"0000-0001-8761-9444","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","last_name":"Shigemoto","first_name":"Ryuichi","full_name":"Shigemoto, Ryuichi"}],"department":[{"_id":"RySh"},{"_id":"PeJo"}],"related_material":{"link":[{"relation":"press_release","url":"https://ista.ac.at/en/news/neuronal-insights-flash-and-freeze-fracture/","description":"News on ISTA Website"}],"record":[{"id":"13173","relation":"research_data","status":"public"},{"status":"public","relation":"dissertation_contains","id":"19271"}]},"acknowledgement":"We thank Erwin Neher and Ipe Ninan for critical comments on the manuscript. This project has received funding from the European Research Council (ERC) and European Commission, under the European Union’s Horizon 2020 research and innovation program (ERC grant agreement no. 694539 to R.S. and the Marie Skłodowska-Curie grant agreement no. 665385 to C.Ö.). This study was supported by the Cooperative Study Program of Center for Animal Resources and Collaborative Study of NINS. We thank Kohgaku Eguchi for statistical analysis, Yu Kasugai for additional EM imaging, Robert Beattie for the design of the slice recovery chamber for Flash and Freeze experiments, Todor Asenov from the ISTA machine shop for custom part preparations for high-pressure freezing, the ISTA preclinical facility for animal caretaking, and the ISTA EM facilities for technical support.","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","publication":"Proceedings of the National Academy of Sciences of the United States of America","language":[{"iso":"eng"}],"ddc":["570"],"tmp":{"legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","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)"},"citation":{"apa":"Koppensteiner, P., Bhandari, P., Önal, C., Borges Merjane, C., Le Monnier, E., Roy, U., … Shigemoto, R. (2024). GABAB receptors induce phasic release from medial habenula terminals through activity-dependent recruitment of release-ready vesicles. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. National Academy of Sciences. <a href=\"https://doi.org/10.1073/pnas.2301449121\">https://doi.org/10.1073/pnas.2301449121</a>","mla":"Koppensteiner, Peter, et al. “GABAB Receptors Induce Phasic Release from Medial Habenula Terminals through Activity-Dependent Recruitment of Release-Ready Vesicles.” <i>Proceedings of the National Academy of Sciences of the United States of America</i>, vol. 121, no. 8, e2301449121, National Academy of Sciences, 2024, doi:<a href=\"https://doi.org/10.1073/pnas.2301449121\">10.1073/pnas.2301449121</a>.","ieee":"P. Koppensteiner <i>et al.</i>, “GABAB receptors induce phasic release from medial habenula terminals through activity-dependent recruitment of release-ready vesicles,” <i>Proceedings of the National Academy of Sciences of the United States of America</i>, vol. 121, no. 8. National Academy of Sciences, 2024.","chicago":"Koppensteiner, Peter, Pradeep Bhandari, Cihan Önal, Carolina Borges Merjane, Elodie Le Monnier, Utsa Roy, Yukihiro Nakamura, et al. “GABAB Receptors Induce Phasic Release from Medial Habenula Terminals through Activity-Dependent Recruitment of Release-Ready Vesicles.” <i>Proceedings of the National Academy of Sciences of the United States of America</i>. National Academy of Sciences, 2024. <a href=\"https://doi.org/10.1073/pnas.2301449121\">https://doi.org/10.1073/pnas.2301449121</a>.","ista":"Koppensteiner P, Bhandari P, Önal C, Borges Merjane C, Le Monnier E, Roy U, Nakamura Y, Sadakata T, Sanbo M, Hirabayashi M, Rhee J, Brose N, Jonas PM, Shigemoto R. 2024. GABAB receptors induce phasic release from medial habenula terminals through activity-dependent recruitment of release-ready vesicles. Proceedings of the National Academy of Sciences of the United States of America. 121(8), e2301449121.","ama":"Koppensteiner P, Bhandari P, Önal C, et al. GABAB receptors induce phasic release from medial habenula terminals through activity-dependent recruitment of release-ready vesicles. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. 2024;121(8). doi:<a href=\"https://doi.org/10.1073/pnas.2301449121\">10.1073/pnas.2301449121</a>","short":"P. Koppensteiner, P. Bhandari, C. Önal, C. Borges Merjane, E. Le Monnier, U. Roy, Y. Nakamura, T. Sadakata, M. Sanbo, M. Hirabayashi, J. Rhee, N. Brose, P.M. Jonas, R. Shigemoto, Proceedings of the National Academy of Sciences of the United States of America 121 (2024)."},"file":[{"relation":"main_file","checksum":"b25b2a057c266ff317a48b0d54d6fc8a","date_updated":"2024-03-12T13:42:42Z","content_type":"application/pdf","success":1,"access_level":"open_access","file_size":13648221,"creator":"dernst","file_name":"2024_PNAS_Koppensteiner.pdf","file_id":"15110","date_created":"2024-03-12T13:42:42Z"}],"publisher":"National Academy of Sciences","intvolume":"       121","issue":"8","article_number":"e2301449121","file_date_updated":"2024-03-12T13:42:42Z","article_processing_charge":"Yes (in subscription journal)","day":"20","date_published":"2024-02-20T00:00:00Z","external_id":{"pmid":["38346189"],"isi":["001208567300006"]},"type":"journal_article","volume":121,"has_accepted_license":"1","doi":"10.1073/pnas.2301449121","publication_identifier":{"issn":["0027-8424"],"eissn":["1091-6490"]},"month":"02","quality_controlled":"1","article_type":"original","oa_version":"Published Version","scopus_import":"1","date_updated":"2026-08-20T22:30:35Z","pmid":1,"project":[{"grant_number":"694539","name":"In situ analysis of single channel subunit composition in neurons: physiological implication in synaptic plasticity and behaviour","call_identifier":"H2020","_id":"25CA28EA-B435-11E9-9278-68D0E5697425"},{"name":"International IST Doctoral Program","grant_number":"665385","call_identifier":"H2020","_id":"2564DBCA-B435-11E9-9278-68D0E5697425"}],"year":"2024","OA_type":"hybrid","publication_status":"published","APC_amount":"5887,8 EUR","license":"https://creativecommons.org/licenses/by-nc-nd/4.0/","isi":1,"corr_author":"1","title":"GABAB receptors induce phasic release from medial habenula terminals through activity-dependent recruitment of release-ready vesicles","status":"public","_id":"15084","oa":1,"date_created":"2024-03-05T09:23:55Z","abstract":[{"lang":"eng","text":"GABAB receptor (GBR) activation inhibits neurotransmitter release in axon terminals in the brain, except in medial habenula (MHb) terminals, which show robust potentiation. However, mechanisms underlying this enigmatic potentiation remain elusive. Here, we report that GBR activation on MHb terminals induces an activity-dependent transition from a facilitating, tonic to a depressing, phasic neurotransmitter release mode. This transition is accompanied by a 4.1-fold increase in readily releasable vesicle pool (RRP) size and a 3.5-fold increase of docked synaptic vesicles (SVs) at the presynaptic active zone (AZ). Strikingly, the depressing phasic release exhibits looser coupling distance than the tonic release. Furthermore, the tonic and phasic release are selectively affected by deletion of synaptoporin (SPO) and Ca\r\n            <jats:sup>2+</jats:sup>\r\n            -dependent activator protein for secretion 2 (CAPS2), respectively. SPO modulates augmentation, the short-term plasticity associated with tonic release, and CAPS2 retains the increased RRP for initial responses in phasic response trains. The cytosolic protein CAPS2 showed a SV-associated distribution similar to the vesicular transmembrane protein SPO, and they were colocalized in the same terminals. We developed the “Flash and Freeze-fracture” method, and revealed the release of SPO-associated vesicles in both tonic and phasic modes and activity-dependent recruitment of CAPS2 to the AZ during phasic release, which lasted several minutes. Overall, these results indicate that GBR activation translocates CAPS2 to the AZ along with the fusion of CAPS2-associated SVs, contributing to persistency of the RRP increase. Thus, we identified structural and molecular mechanisms underlying tonic and phasic neurotransmitter release and their transition by GBR activation in MHb terminals."}]},{"month":"04","quality_controlled":"1","article_type":"original","publication_identifier":{"eissn":["2050-084X"]},"has_accepted_license":"1","volume":10,"doi":"10.7554/ELIFE.68274","external_id":{"isi":["000651761700001"],"pmid":["33913808"]},"type":"journal_article","article_number":"e68274","file_date_updated":"2021-05-31T09:43:09Z","article_processing_charge":"No","day":"29","date_published":"2021-04-29T00:00:00Z","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>","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>.","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>"},"publisher":"eLife Sciences Publications","file":[{"date_created":"2021-05-31T09:43:09Z","creator":"cziletti","file_name":"2021_eLife_Bhandari.pdf","file_id":"9440","content_type":"application/pdf","date_updated":"2021-05-31T09:43:09Z","success":1,"access_level":"open_access","file_size":8174719,"checksum":"6ebcb79999f889766f7cd79ee134ad28","relation":"main_file"}],"intvolume":"        10","ddc":["570"],"language":[{"iso":"eng"}],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publication":"eLife","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"author":[{"id":"45EDD1BC-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-0863-4481","full_name":"Bhandari, Pradeep","first_name":"Pradeep","last_name":"Bhandari"},{"first_name":"David H","last_name":"Vandael","full_name":"Vandael, David H","orcid":"0000-0001-7577-1676","id":"3AE48E0A-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Diego","last_name":"Fernández-Fernández","full_name":"Fernández-Fernández, Diego"},{"last_name":"Fritzius","first_name":"Thorsten","full_name":"Fritzius, Thorsten"},{"id":"42E121A4-F248-11E8-B48F-1D18A9856A87","full_name":"Kleindienst, David","last_name":"Kleindienst","first_name":"David"},{"first_name":"Hüseyin C","last_name":"Önal","full_name":"Önal, Hüseyin C","orcid":"0000-0002-2771-2011","id":"4659D740-F248-11E8-B48F-1D18A9856A87"},{"id":"3786AB44-F248-11E8-B48F-1D18A9856A87","full_name":"Montanaro-Punzengruber, Jacqueline-Claire","first_name":"Jacqueline-Claire","last_name":"Montanaro-Punzengruber"},{"last_name":"Gassmann","first_name":"Martin","full_name":"Gassmann, Martin"},{"full_name":"Jonas, Peter M","first_name":"Peter M","last_name":"Jonas","id":"353C1B58-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-5001-4804"},{"full_name":"Kulik, Akos","first_name":"Akos","last_name":"Kulik"},{"full_name":"Bettler, Bernhard","last_name":"Bettler","first_name":"Bernhard"},{"first_name":"Ryuichi","last_name":"Shigemoto","full_name":"Shigemoto, Ryuichi","orcid":"0000-0001-8761-9444","id":"499F3ABC-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Koppensteiner","first_name":"Peter","full_name":"Koppensteiner, Peter","orcid":"0000-0002-3509-1948","id":"3B8B25A8-F248-11E8-B48F-1D18A9856A87"}],"ec_funded":1,"department":[{"_id":"RySh"},{"_id":"PeJo"}],"related_material":{"record":[{"status":"public","relation":"dissertation_contains","id":"19271"},{"status":"public","relation":"dissertation_contains","id":"9562"}],"link":[{"relation":"earlier_version","url":"https://doi.org/10.1101/2020.04.16.045112"}]},"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.","oa":1,"date_created":"2021-05-30T22:01:23Z","abstract":[{"text":"The synaptic connection from medial habenula (MHb) to interpeduncular nucleus (IPN) is critical for emotion-related behaviors and uniquely expresses R-type Ca2+ channels (Cav2.3) and auxiliary GABAB receptor (GBR) subunits, the K+-channel tetramerization domain-containing proteins (KCTDs). Activation of GBRs facilitates or inhibits transmitter release from MHb terminals depending on the IPN subnucleus, but the role of KCTDs is unknown. We therefore examined the localization and function of Cav2.3, GBRs, and KCTDs in this pathway in mice. We show in heterologous cells that KCTD8 and KCTD12b directly bind to Cav2.3 and that KCTD8 potentiates Cav2.3 currents in the absence of GBRs. In the rostral IPN, KCTD8, KCTD12b, and Cav2.3 co-localize at the presynaptic active zone. Genetic deletion indicated a bidirectional modulation of Cav2.3-mediated release by these KCTDs with a compensatory increase of KCTD8 in the active zone in KCTD12b-deficient mice. The interaction of Cav2.3 with KCTDs therefore scales synaptic strength independent of GBR activation.","lang":"eng"}],"title":"GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals","status":"public","_id":"9437","isi":1,"publication_status":"published","license":"https://creativecommons.org/licenses/by/4.0/","project":[{"grant_number":"694539","name":"In situ analysis of single channel subunit composition in neurons: physiological implication in synaptic plasticity and behaviour","_id":"25CA28EA-B435-11E9-9278-68D0E5697425","call_identifier":"H2020"},{"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","call_identifier":"H2020","name":"International IST Doctoral Program","grant_number":"665385"}],"pmid":1,"year":"2021","date_updated":"2026-08-20T22:31:03Z","scopus_import":"1","oa_version":"Published Version"}]