Endolysosomal TPCs regulate social behavior by controlling oxytocin secretion

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 influx, but is also dependent on Ca release from intracellular stores, which primes LDCVs...

Full description

Saved in:

Bibliographic Details
Published in:	Proceedings of the National Academy of Sciences - PNAS 2023-02, Vol.120 (7), p.e2213682120-e2213682120
Main Authors:	Martucci, Lora L, Launay, Jean-Marie, Kawakami, Natsuko, Sicard, Cécile, Desvignes, Nathalie, Dakouane-Giudicelli, Mbarka, Spix, Barbara, Têtu, Maude, Gilmaire, Franck-Olivier, Paulcan, Sloane, Callebert, Jacques, Vaillend, Cyrille, Bracher, Franz, Grimm, Christian, Fossier, Philippe, de la Porte, Sabine, Sakamoto, Hirotaka, Morris, John, Galione, Antony, Granon, Sylvie, Cancela, José-Manuel
Format:	Article
Language:	eng
Subjects:	Adenine Animals Biological Sciences Calcium Calcium (intracellular) Calcium - metabolism Calcium Channels Calcium Channels - metabolism Calcium influx Calcium ions Calcium Signaling Calcium Signaling - physiology Calcium signalling Dense core vesicles Exocytosis Glutamic acid receptors (metabotropic) Hypothalamus Life Sciences Lysosomes Lysosomes - metabolism Mammals Mammals - metabolism Maternal behavior Mice Mice, Knockout NAADP NADP NADP - metabolism Neurobiology Neurons and Cognition Neuropeptides Nicotinic acid Oxytocin Oxytocin - metabolism Priming Secretion Social behavior Vesicles
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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 influx, but is also dependent on Ca release from intracellular stores, which primes LDCVs for exocytosis. Despite its importance, critical aspects of the Ca -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 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.
ISSN:	0027-8424 1091-6490