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However, the mechanisms underlying the formation and maintenance of social memory remain poorly understood. In this study, we demonstrate that social interaction with unfamiliar mouse induces \u03b1- and \u03b3-secretase-dependent proteolysis of Neuroligin 1 (NLG1) in the ventral hippocampus (vHPC). The intracellular hydrolysate fragment, NLG1-CTD, regulates synaptic plasticity, spine strengthening, and the maintenance of social memory through its PDZ binding domain (PBD) and the cofilin signaling pathway. Both \u03b3-secretase inhibition and deletion of the secretase recognition site on NLG1 prevent cofilin phosphorylation and impair the maintenance of social memory by inhibiting the production of NLG1-CTD. Injection of the Tat-PBD peptide into the vHPC inhibits cofilin activity and rescues deficits in social memory maintenance in mouse models. Additionally, our findings indicate that deficits in maintaining memory for sequentially presented social objects within a short temporal interval may be associated with insufficient levels of NLG1-CTD. Supplementation of Tat-PBD into the vHPC promotes maturation of dendritic spines and restores the maintenance of memory for the second social object. We also discovered that NLG1-CTD\/PBD may play a role in maintaining novel object recognition memory. In summary, this work uncovers a novel mechanism that links extracellular and intracellular signal transduction processes to synaptic remodeling during learning and memory maintenance, providing a systematic perspective that connects memory formation, maintenance, and synaptic structural and functional plasticity.<\/jats:p>","DOI":"10.1038\/s41392-025-02467-6","type":"journal-article","created":{"date-parts":[[2025,11,23]],"date-time":"2025-11-23T23:02:59Z","timestamp":1763938979000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Social memory maintenance relies on social interaction-induced proteolytic products of neuroligin 1"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0421-8050","authenticated-orcid":false,"given":"An","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingcan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaoyun","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinglei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingjie","family":"Bian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengyan","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuqi","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moyi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengping","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9179-4787","authenticated-orcid":false,"given":"Wei","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,24]]},"reference":[{"key":"2467_CR1","doi-asserted-by":"crossref","unstructured":"Atkinson, R. 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