Altered social behavior and prefrontal dopaminergic signaling in female Dtnbp1 knockout mice

Schizophrenia is a complex neuropsychiatric disorder associated with genetic variants of the dystrobrevin-binding protein 1 (Dtnbp1) gene. While cognitive deficits in male Dtnbp1 mutant mice are well-documented, the impact of this mutation on female subjects remains underexplored. This study investigated the behavioral and molecular effects of Dtnbp1 deficiency in male and female knockout (Dys^-/-) mice, highlighting sex-specific cognitive, social, and molecular signaling impairments relevant to schizophrenia. Female Dys-/- mice exhibited an anxiolytic phenotype with intact threat memory and normal novel object recognition memory. However, they displayed profound deficits in temporal order recognition memory and multiple domains of social behavior. Conversely, male Dys^-/- mice largely maintained normal social recognition. Molecular analyses revealed dysregulation of the dopaminergic system specifically in the prefrontal cortex (PFC) of female Dys^-/- mice. This dysfunction was characterized by reduced mRNA expression of the dopamine receptors D1 (Drd1) and D2 (Drd2), as well as aberrant activity of canonical (DARPP-32) and noncanonical (GSK3β) signaling pathways. Collectively, these findings demonstrate that dysbindin-1 deficiency drives distinct, female-specific vulnerabilities in behavioral and molecular alterations relevant to neuropsychiatric conditions, providing insight into the sex-dependent pathophysiology of social and cognitive deficits in preclinical models of schizophrenia.