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It has been shown that depression leads to impairments in synaptic plasticity, such as impaired long-term potentiation (LTP) in the prefrontal cortex (PFC). A recent study reported that administration of agomelatine, a melatonin receptor agonist and 5-hydroxytryptamine (5-HT) 2C antagonist, which may be involved in synaptic functions, for 1\u00a0week has a rapid antidepressive effect. Moreover, the mechanism of Glycogen synthase kinase 3\u03b2 (GSK3\u03b2), regulated by signal transducer and activator of transcription 3 (STAT3), may play an important role in the synapse-related pathological mechanisms of depression. Hence, we used chronic social defeat stress (CSDS) as an animal model of depression, to investigate whether synaptic plasticity impairment in depression, improved by agomelatine, is mediated through the STAT3 mechanism. The results showed that depressive-like behaviors were reversed after 1 week of agomelatine treatment. Moreover, the impairment of LTP and alteration of spine density were reversed by agomelatine in the PFC. We further applied AG490, an inhibitor of STAT3, to demonstrate that the therapeutic mechanism of agomelatine improves synaptic plasticity through STAT3-regulated phosphorylation of GSK3\u03b2. Taken together, these results demonstrated that STAT3-regulated downstream molecules are potential therapeutic targets for the rapid action of antidepressants.<\/jats:p>","DOI":"10.1007\/s12035-025-05638-2","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T08:48:55Z","timestamp":1766393335000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["STAT3 Signaling Mediates Agomelatine Restoration of Prefrontal Cortex Synaptic Plasticity in Chronic Social Defeat Stress Mice"],"prefix":"10.1007","volume":"63","author":[{"given":"Chi-Wei","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han-Fang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-Ju","family":"Yen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lun-De","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Chang","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsun-Shuo","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yih-Fung","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Hsien","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Ta","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Ching","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,22]]},"reference":[{"issue":"11","key":"5638_CR1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0030442","volume":"3","author":"CD Mathers","year":"2006","unstructured":"Mathers CD, Loncar D (2006) Projections of global mortality and burden of disease from 2002 to 2030. 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