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Article Dans Une Revue Proceedings of the National Academy of Sciences of the United States of America Année : 2023

Endolysosomal TPCs regulate social behavior by controlling oxytocin secretion

Natsuko Kawakami
Maude Têtu
Sloane Paulcan
Cyrille Vaillend
Franz Bracher
Christian Grimm
Hirotaka Sakamoto
John Morris
Antony Galione
Sylvie Granon

Résumé

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 2+ influx, but is also dependent on Ca 2+ release from intracellular stores, which primes LDCVs for exocytosis. Despite its importance, critical aspects of the Ca 2+ -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 2+ 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.

Domaines

Neurobiologie
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Origine : Publication financée par une institution
Licence : CC BY - Paternité

Dates et versions

hal-04050275 , version 1 (06-06-2023)

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Paternité

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Citer

Lora Martucci, Jean-Marie Launay, Natsuko Kawakami, Cécile Sicard, Nathalie Desvignes, et al.. Endolysosomal TPCs regulate social behavior by controlling oxytocin secretion. Proceedings of the National Academy of Sciences of the United States of America, 2023, 120 (7), pp.e2213682120. ⟨10.1073/pnas.2213682120⟩. ⟨hal-04050275⟩
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