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Considering the antidepressant effect of \u03b1-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors activation in the prefrontal cortex, we hypothesized that glycogen synthase kinase 3\u03b2-induced alterations in \u03b1-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors function in the prefrontal cortex participate in depression. Herein, we confirmed that the levels of phosphorylated glycogen synthase kinase 3\u03b2 and GluA1, the latter being a subunit of \u03b1-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, were decreased in the prefrontal cortex of the chronic social defeat stress model mice presenting with depressive-like behaviors. We then found that a glycogen synthase kinase 3\u03b2 (p.S9A) point mutation downregulated GluA1 and induced depressive-like behaviors in mice, whereas an agonist of \u03b1-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, PF-4778574 (2\u00a0mg\/kg) did not reversed the molecular changes. On the other hand, the antidepressant effect of PF-4778574 was dose dependent, and the single administration of PF-4778574 at a lower dose (0.5\u00a0mg\/kg) or of the glycogen synthase kinase 3\u03b2 inhibitor SB216763 (5 and 10\u00a0mg\/kg) did not evoke an antidepressant effect. In contrast, co-treatment with PF-4778574 (0.5\u00a0mg\/kg) and SB216763 (10\u00a0mg\/kg) led to antidepressant effects similar to those of PF-4778574 (2\u00a0mg\/kg). Our results suggest that glycogen synthase kinase 3\u03b2-induced \u03b1-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors dysfunction in the prefrontal cortex is one of the key mechanisms of depression, and the combination of a lower dose of PF-4778574 with SB216763 shows potential as a novel synergistic treatment for depression.<\/jats:p>","DOI":"10.1093\/cercor\/bhad299","type":"journal-article","created":{"date-parts":[[2023,8,11]],"date-time":"2023-08-11T21:47:03Z","timestamp":1691790423000},"page":"10504-10513","source":"Crossref","is-referenced-by-count":3,"title":["Novel synergistic treatment for depression: involvement of GSK3\u03b2-regulated AMPA receptors in the prefrontal cortex of mice"],"prefix":"10.1093","volume":"33","author":[{"given":"Lei","family":"Guo","sequence":"first","affiliation":[{"name":"Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University , Ningbo, Zhejiang 315211 , PR China"},{"name":"School of Basic Medical 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