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The compounds CN2097 and Syn3 both bind to the PDZ3 domain of PSD-95, and Syn3 also binds to an \u03b1-helical region of the protein. Syn3 reduced depression-like behaviors in two mouse models of stress-induced depression; CN2097 had similar but less potent effects. In hippocampal neurons, application of Syn3 enhanced the formation of TrkB\u2013G\u03b1\n            <jats:sub>i1\/3<\/jats:sub>\n            \u2013PSD-95 complexes and potentiated downstream PI3K-Akt-mTOR signaling. In mice subjected to chronic mild stress (CMS), systemic administration of Syn3 reversed the CMS-induced, depression-associated changes in PI3K-Akt-mTOR signaling, dendrite complexity, spine density, and autophagy in the hippocampus and reduced depression-like behaviors. Knocking out G\u03b1\n            <jats:sub>i1\/3<\/jats:sub>\n            in hippocampal neurons prevented the therapeutic effects of Syn3, indicating dependence of these effects on the TrkB pathway. The findings suggest that compounds that induce the formation of PSD-95\u2013TrkB complexes have therapeutic potential to alleviate depression.\n          <\/jats:p>","DOI":"10.1126\/scisignal.adn4556","type":"journal-article","created":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T18:02:20Z","timestamp":1714500140000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":58,"title":["Targeting the postsynaptic scaffolding protein PSD-95 enhances BDNF signaling to mitigate depression-like behaviors in mice"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4902-5498","authenticated-orcid":true,"given":"Xin","family":"Shi","sequence":"first","affiliation":[{"name":"Clinical Research Center of Neurological Disease, Second Affiliated Hospital of Soochow University, Institution of Neuroscience, Soochow University, Suzhou 215123, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3076-5090","authenticated-orcid":true,"given":"Xiao-zhong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Clinical Research Center of Neurological Disease, Second Affiliated Hospital of Soochow University, Institution of Neuroscience, Soochow University, Suzhou 215123, China."},{"name":"Department of Orthopedics, Second Affiliated Hospital of Soochow University, Suzhou 215004, Jiangsu, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0758-1907","authenticated-orcid":true,"given":"Gang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3594-1885","authenticated-orcid":true,"given":"Wei-feng","family":"Luo","sequence":"additional","affiliation":[{"name":"Clinical Research Center of Neurological Disease, Second Affiliated Hospital of Soochow University, Institution of Neuroscience, Soochow University, Suzhou 215123, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4014-3140","authenticated-orcid":true,"given":"Chengyu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Case Western Reserve University, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian-ju","family":"He","sequence":"additional","affiliation":[{"name":"Clinical Research Center of Neurological Disease, Second Affiliated Hospital of Soochow University, Institution of Neuroscience, Soochow University, Suzhou 215123, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7016-572X","authenticated-orcid":true,"given":"Mandar T.","family":"Naik","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Cell Biology &amp; 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