{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T18:47:16Z","timestamp":1792176436895,"version":"4.4.0"},"reference-count":35,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"42","funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82204357"],"award-info":[{"award-number":["82204357"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81803505"],"award-info":[{"award-number":["81803505"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004608","name":"National Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20241858"],"award-info":[{"award-number":["BK20241858"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004608","name":"National Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20231267"],"award-info":[{"award-number":["BK20231267"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,10,16]]},"abstract":"<jats:p>\n                    Astrocyte pathology is increasingly recognized as a key factor in the pathogenesis of major depressive disorder (MDD), where disrupted glutamate clearance and impaired neuron-glia interactions contribute to synaptic dysfunction. However, the molecular mechanisms leading to astrocyte loss remain largely undefined. Mitochondrial dysfunction is a hallmark of MDD, yet most studies have focused on neuronal mitochondria, leaving astrocytic mitochondrial dynamics insufficiently investigated. Here, we identify mitofusin-2 (MFN2)\u2013associated astrocyte dysfunction in depression. SMART-seq profiling of hippocampal astrocytes from chronic social defeat stress (CSDS) mice revealed\n                    <jats:italic toggle=\"yes\">Mfn2<\/jats:italic>\n                    up-regulation, accompanied by excessive mitochondrial fusion, impaired mitophagy, and astrocyte loss. Elevated\n                    <jats:italic toggle=\"yes\">MFN2<\/jats:italic>\n                    expression was detected in plasma, postmortem brain tissue, and iPSC-derived astrocytes from patients with MDD. Astrocyte-specific knockdown of\n                    <jats:italic toggle=\"yes\">Mfn2<\/jats:italic>\n                    restored mitochondrial morphology and mitophagy, thereby preserving astrocyte viability and alleviating depressive-like behaviors. Using mass spectrometry\u2013based label-free proteomics, in vivo calcium imaging, and functional assays, we demonstrated that \u03b2-arrestin2 deficiency reduced STAT1 stability, releasing its transcriptional repression on\n                    <jats:italic toggle=\"yes\">Mfn2<\/jats:italic>\n                    . Normalization of MFN2 expression through astrocytic\n                    <jats:italic toggle=\"yes\">Mfn2<\/jats:italic>\n                    knockdown or\n                    <jats:italic toggle=\"yes\">Stat1<\/jats:italic>\n                    overexpression reduced extracellular glutamate accumulation and prevented neuronal hyperexcitability in CSDS mice. Collectively, our findings define astrocytic MFN2-associated astrocyte dysfunction as a central pathological event in depressive behaviors, with the \u03b2-arrestin2\u2013STAT1 pathway acting as an upstream regulatory mechanism. This work reveals an astrocytic pathway in depression and highlights a potential therapeutic target that directly addresses astrocyte pathology, beyond the neuron-centered focus of current antidepressant treatments.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aed8795","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:58:53Z","timestamp":1792173533000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["MFN2-associated astrocyte dysfunction contributes to neuronal hyperexcitability and depressive-like behaviors"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0395-0568","authenticated-orcid":true,"given":"Feng-xia","family":"Ma","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo-yan","family":"Fang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-xin","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shen-han","family":"Xu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-xin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-xiao","family":"Liu","sequence":"additional","affiliation":[{"name":"Changzhou Second People\u2019s Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4315-0351","authenticated-orcid":true,"given":"Chen","family":"Qiao","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang 212001, Jiangsu, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5813-9368","authenticated-orcid":true,"given":"Qiu-ling","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Nursing, Nanjing University of Chinese Medicine, Nanjing 210023, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6493-1467","authenticated-orcid":true,"given":"Lei","family":"Cao","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China."},{"name":"Changzhou Second People\u2019s Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, 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