Endolysosomal TPCs regulate social behavior by controlling oxytocin secretion

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Oxytocin (OT) regulates social behavior and is stored in large dense-cored vesicles (LDCVs).
• OT secretion depends on calcium (Ca²⁺) influx and intracellular Ca²⁺ release, which primes LDCVs for exocytosis.
• The precise Ca²⁺-dependent mechanisms priming OT secretion remain incompletely understood.

Purpose of the Study:

• To elucidate the role of lysosomes and two-pore channels (TPCs) in regulating oxytocin secretion.
• To investigate the Ca²⁺ signaling pathways involved in priming neuropeptide vesicles for release.
• To determine the impact of TPC function on social behavior.

Main Methods:

• Investigated lysosome-LDCV interactions in hypothalamic neurons.
• Utilized TPC knockout mice to assess OT levels and secretion.
• Examined the effects of TPC activators (nicotinic acid adenine dinucleotide phosphate, TPC2-A1-N) and antagonists (Ned-19).
• Assessed maternal and social behaviors in wild-type and TPC knockout mice.

Main Results:

• Lysosomes were found to surround dendritic LDCVs.
• Direct activation of TPCs provided critical Ca²⁺ signals that prime OT release by increasing the releasable LDCV pool.
• TPC knockout mice exhibited reduced plasma OT levels and impaired hypothalamic OT secretion.
• Activation of metabotropic glutamate receptors recruited TPCs to sustain somatodendritic OT release.
• Mice lacking TPCs showed impaired social and maternal behaviors, which were restored by OT administration.

Conclusions:

• Lysosomes and TPCs play an unexpected but crucial role in neuropeptide secretion by priming LDCVs.
• TPC-mediated Ca²⁺ signaling is essential for regulating the releasable pool of OT vesicles.
• Dysregulation of TPCs impairs social behavior, highlighting their importance in neuroendocrine regulation of social interactions.