OXT neuron-specific CAPS2 deficiency in mice impairs hippocampal plasticity and long-term memory through reduced ERK phosphorylation in the ventral hippocampus

OXT neuron-specific CAPS2 deficiency in mice impairs hippocampal plasticity and long-term memory through reduced ERK phosphorylation in the ventral hippocampus | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL European Journal of Neuroscience This is a preprint and has not been peer reviewed. Data may be preliminary. 5 December 2025 V1 Latest version Share on OXT neuron-specific CAPS2 deficiency in mice impairs hippocampal plasticity and long-term memory through reduced ERK phosphorylation in the ventral hippocampus Authors : Wakana Nagano , Junpei Takahashi , Daisuke Yamada , Yoshitake Sano , Teiichi Furuichi , and Akiyoshi Saitoh 0000-0001-8617-2441 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176494000.08749304/v1 254 views 216 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Oxytocin (OXT), a neuropeptide produced in the paraventricular nucleus (PVN) of the hypothalamus, regulates social behavior, 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. Behavioral analyses revealed that Caps2 cKO mice exhibited deficits in long-term memory in the novel object recognition (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 signaling in cognitive function and suggest its potential relevance to the pathogenesis of memory disorders such as Alzheimer’s disease. Supplementary Material File (caps2 manuscript no figure.docx) Download 79.83 KB Information & Authors Information Version history V1 Version 1 05 December 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Collection European Journal of Neuroscience Keywords ca2+-dependent activator protein for secretion cognitive function learning and memory oxytocin Authors Affiliations Wakana Nagano Tokyo University of Science - Katsushika Campus View all articles by this author Junpei Takahashi Tokyo University of Science - Katsushika Campus View all articles by this author Daisuke Yamada Tokyo University of Science - Katsushika Campus View all articles by this author Yoshitake Sano Tokyo University of Science View all articles by this author Teiichi Furuichi Tokyo University of Science View all articles by this author Akiyoshi Saitoh 0000-0001-8617-2441 [email protected] Tokyo University of Science - Katsushika Campus View all articles by this author Metrics & Citations Metrics Article Usage 254 views 216 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Wakana Nagano, Junpei Takahashi, Daisuke Yamada, et al. OXT neuron-specific CAPS2 deficiency in mice impairs hippocampal plasticity and long-term memory through reduced ERK phosphorylation in the ventral hippocampus. Authorea . 05 December 2025. DOI: https://doi.org/10.22541/au.176494000.08749304/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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