By mimicking the overexpression of the disease‐associated G allele specifically in the PFC of wild‐type mice, we found that PAXIP1‐AS1‐G overexpression induces a spectrum of behavioral abnormalities, including anxiety‐ and depression‐like behaviors, working memory deficits, sensorimotor gating impairments, and reduced social preference. This evidence concerns the gene PAXIP1 and major depressive disorder.