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However, the molecular mechanisms underlying the pathogenesis of MDD remain largely unknown. In the present study, we demonstrate that chronic stress\u2014an established inducer of depression-like behaviors in animal models\u2014upregulates the expression of protein kinase C and casein kinase substrate in neurons protein 2 (PACSIN2) in the hippocampal dCA1 region, a key regulator of the actin cytoskeleton and endocytic processes. The overexpression of PACSIN2 in CA1 hippocampal pyramidal neurons may increase the susceptibility to stress stimulation in rats through physical interactions with dynamin and cooperative modulation of the expression of postsynaptic membrane GluA1 AMPA receptors. Selective knockdown of PACSIN2 in the dCA1 hippocampal region of depressed rats significantly enhanced synaptic transmission, ultimately ameliorating depression-like behaviors. These findings provide direct evidence that abnormal function of hippocampal neurons resulting from perturbations in neuroplasticity may be involved in the pathogenesis of MDD. Moreover, PACSIN2 may serve as one of the underlying molecular controls through which chronic stress induces synaptic loss and dysfunction and the resulting behavioral disorders.<\/jats:p>","DOI":"10.1038\/s41401-026-01790-0","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T14:29:33Z","timestamp":1778164173000},"page":"2358-2376","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PACSIN2-mediated synaptic injury contributes to behavioral disorders caused by chronic stress"],"prefix":"10.1038","volume":"47","author":[{"given":"Chang-min","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-hang","family":"Yi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Lan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-yan","family":"Lou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-cheng","family":"Jian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei-jian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-yan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"1790_CR1","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1001\/jamapsychiatry.2017.4602","volume":"75","author":"DS Hasin","year":"2018","unstructured":"Hasin DS, Sarvet AL, Meyers JL, Saha TD, Ruan WJ, Stohl M, et al. 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