Acute metformin treatment increased social sniffing in male but not female BTBR mice

Autism spectrum disorders (ASDs) are characterized by social deficits and restrictive-repetitive behaviors. Metformin has recently been investigated for its potential behavioral effects in ASD models. This study examined the acute effects of metformin on social interaction preferences and marble burying in male and female BTBR T + Itpr3tf/J (BTBR) mice, with C57BL/6J and 129S1/SvImJ mice included as strain controls. The mice received a single intraperitoneal injection of metformin (0 mg, 75 mg, or 150 mg/kg), and the effects were compared using three-chamber social preference and marble burying tests. Acute metformin increased not only social interaction preferences, as determined by differences in time spent in chambers, but also by differences in social sniffing time in male BTBR mice at 150 mg/kg. Surprisingly, it did not alter sociability preferences in BTBR females or in C57BL/6J or 129S1/SvImJ mice. In C57BL/6J females, metformin reduced chamber entries and marble burying, whereas males were unaffected. Progesterone and corticosterone levels were measured in BTBR and C57BL/6J serum collected after behavioral testing, and their levels were unaffected by metformin treatment. These findings indicate that metformin acutely produces modest, beneficial behavioral effects in male BTBR mice, which otherwise exhibit social interaction deficits that are translationally relevant to ASD.