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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,2,14]]},"abstract":"<jats:p>\n                    Oxytocin (OT) is a prominent regulator of many aspects of mammalian social behavior and stored in large dense-cored vesicles (LDCVs) in hypothalamic neurons. It is released in response to activity-dependent Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx, but is also dependent on Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release from intracellular stores, which primes LDCVs for exocytosis. Despite its importance, critical aspects of the Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -dependent mechanisms of its secretion remain to be identified. Here we show that lysosomes surround dendritic LDCVs, and that the direct activation of endolysosomal two-pore channels (TPCs) provides the critical Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signals to prime OT release by increasing the releasable LDCV pool without directly stimulating exocytosis. We observed a dramatic reduction in plasma OT levels in TPC knockout mice, and impaired secretion of OT from the hypothalamus demonstrating the importance of priming of neuropeptide vesicles for activity-dependent release. Furthermore, we show that activation of type 1 metabotropic glutamate receptors sustains somatodendritic OT release by recruiting TPCs. The priming effect could be mimicked by a direct application of nicotinic acid adenine dinucleotide phosphate, the endogenous messenger regulating TPCs, or a selective TPC2 agonist, TPC2-A1-N, or blocked by the antagonist Ned-19. Mice lacking TPCs exhibit impaired maternal and social behavior, which is restored by direct OT administration. This study demonstrates an unexpected role for lysosomes and TPCs in controlling neuropeptide secretion, and in regulating social behavior.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2213682120","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T15:24:21Z","timestamp":1675697061000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":19,"title":["Endolysosomal TPCs regulate social behavior by controlling oxytocin secretion"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5335-2822","authenticated-orcid":false,"given":"Lora L.","family":"Martucci","sequence":"first","affiliation":[{"name":"Neuroscience Paris-Saclay Institute, CNRS UMR 9197, Paris-Sud University, Paris-Saclay University, Saclay 91400, France"},{"name":"Universit\u00e9 Paris-Saclay, Universit\u00e9 de Versailles Saint-Quentin-en-Yvelines, Inserm, Evolution of Neuromuscular Diseases: Innovative Concepts and Practices, Versailles 78000, France"},{"name":"Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4809-1020","authenticated-orcid":false,"given":"Jean-Marie","family":"Launay","sequence":"additional","affiliation":[{"name":"INSERM UMR-S 942, H\u00f4pital Lariboisi\u00e8re, Paris Cedex 10 75475, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1183-8381","authenticated-orcid":false,"given":"Natsuko","family":"Kawakami","sequence":"additional","affiliation":[{"name":"Ushimado Marine Institute, Graduate School of Natural Science and Technology, Okayama University, Ushimado, Setouchi, Okayama 701-4303, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9cile","family":"Sicard","sequence":"additional","affiliation":[{"name":"Neuroscience Paris-Saclay Institute, CNRS UMR 9197, Paris-Sud University, Paris-Saclay University, Saclay 91400, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Desvignes","sequence":"additional","affiliation":[{"name":"Neuroscience Paris-Saclay Institute, CNRS UMR 9197, Paris-Sud University, Paris-Saclay University, Saclay 91400, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0169-0037","authenticated-orcid":false,"given":"Mbarka","family":"Dakouane-Giudicelli","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Universit\u00e9 de Versailles Saint-Quentin-en-Yvelines, Inserm, Evolution of Neuromuscular Diseases: Innovative Concepts and Practices, Versailles 78000, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Spix","sequence":"additional","affiliation":[{"name":"Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine Ludwig-Maximilians-University, Munich 80336, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5185-962X","authenticated-orcid":false,"given":"Maude","family":"T\u00eatu","sequence":"additional","affiliation":[{"name":"Neuroscience Paris-Saclay Institute, CNRS UMR 9197, Paris-Sud University, Paris-Saclay University, Saclay 91400, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franck-Olivier","family":"Gilmaire","sequence":"additional","affiliation":[{"name":"Neuroscience Paris-Saclay Institute, CNRS UMR 9197, Paris-Sud University, Paris-Saclay University, Saclay 91400, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3667-9807","authenticated-orcid":false,"given":"Sloane","family":"Paulcan","sequence":"additional","affiliation":[{"name":"Neuroscience Paris-Saclay Institute, CNRS UMR 9197, Paris-Sud University, Paris-Saclay University, Saclay 91400, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5622-851X","authenticated-orcid":false,"given":"Jacques","family":"Callebert","sequence":"additional","affiliation":[{"name":"Laboratoire de Biochimie et Biologie Mol\u00e9culaire, H\u00f4pital Lariboisi\u00e8re, Paris 75010, France"},{"name":"Inserm UMR-S 1144 Universit\u00e9s Paris Descartes-Paris Diderot, Optimisation Th\u00e9rapeutique en Neuropsychopharmacologie - 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