Oxytocin Neuron-Specific CAPS2 Deficiency in Mice Impairs Hippocampal Plasticity and Long-Term Memory Through Reduced...

Oxytocin (OXT), a neuropeptide produced in the paraventricular nucleus (PVN) of the hypothalamus, regulates social behaviour, stress responses, and memory. Our previous studies demonstrated that intracerebroventricular administration of OXT ameliorates amyloid-β-induced cognitive deficits and that selective activation of PVN OXT neurons enhances memory performance. These findings suggest that endogenous OXT secretion is essential for normal memory processing and that its impairment may lead to cognitive dysfunction. To test this hypothesis, we generated oxytocin neuron-specific conditional knockout (cKO) mice for the Ca²⁺-dependent activator protein for secretion 2 (CAPS2) by crossing Caps2-floxed mice with oxytocin-iCre mice. In these mice, OXT exocytosis was selectively impaired in OXT neurons. Behavioural analyses revealed that Caps2 cKO mice exhibited deficits in long-term memory in the novel object recognition test (NORT) and passive avoidance tests, whereas short-term spatial memory assessed by the Y-maze test remained unaffected. Electrophysiological recordings further showed that hippocampal long-term potentiation was markedly attenuated in Caps2 cKO mice. Consistently, phosphorylated ERK levels in the ventral hippocampus were significantly reduced following the NORT. These findings demonstrate that CAPS2-dependent OXT release is critical for long-term memory formation and hippocampal synaptic plasticity. Our results provide new insight into the physiological role of endogenous OXT signalling in cognitive function and suggest its potential relevance to the pathogenesis of memory disorders such as Alzheimer's disease.