Psilocybin restores social novelty investigation in male SAPAP3 knockout mice and engages prefrontal–hippocampal circuitry

Obsessive-compulsive disorder (OCD) remains difficult to treat, and evidence indicates that social dysfunction, common across obsessive-compulsive and related disorders, is an under-recognized clinical burden. SAPAP3 knockout (KO) mice, a well-established model of compulsive behavior, exhibit social abnormalities, suggesting broader disruptions in circuits relevant to social cognition. Here, we investigated whether psilocybin, a serotonergic psychedelic with emerging therapeutic potential, can restore social behavior in SAPAP3 KO mice and whether behavioral rescue is associated with modulation of neural activity. Male and female SAPAP3 KO mice and wild-type littermates received a 1 mg/kg psilocybin intraperitoneal injection, and social behavior was assessed seven days later using the three-chamber social interaction test. Psilocybin produced a male-specific, enduring restoration of novel-mouse-directed investigation during social recognition/novelty testing. Immunohistochemical quantification of c-Fos revealed that psilocybin increased neural activation in the medial prefrontal cortex and hippocampus regardless of genotype. Only infralimbic c-Fos levels correlated with improved social recognition/novelty behavior in male SAPAP3 KO mice, identifying infralimbic recruitment as a key correlate of therapeutic rescue. Psilocybin did not alter c-Fos in the nucleus accumbens, basolateral amygdala, or dorsal striatum. These findings demonstrate that psilocybin exerts domain-specific, enduring effects on social cognition in an established model of compulsive-like behavior, potentially involving prefrontal plasticity-related mechanisms. Given the lack of pharmacological treatments targeting social dysfunction in OCD and associated neuropsychiatric disorders, these results highlight psilocybin as a promising candidate for improving social-cognitive outcomes in disorders characterized by repetitive behaviors and social impairment.