LF-rTMS ameliorates social dysfunction of FMR1^-/- mice via modulating Akt/GSK-3β signaling

Autism spectrum disorders (ASD) are a group of neurological disorders which affect approximately 1% of children around the world. Social dysfunction is one of the two core syndromes of ASD, and still lacks effective treatment. Transcranial magnetic stimulation (TMS) is a noninvasive and safe procedure that uses magnetic fields to modulate neural activity. Whether it were effective in modulating social function remains unclear. By using 3-chamber test, ultrasonic vocalization recording and Western-blotting, we demonstrated that FMR1 (fragile X mental retardation protein) mutant mice, a model of ASD, exhibited obvious defects in social preference and ultrasonic communication. In addition, we detected increase of p-Akt (S473) and p-GSK-3β (S9), and decrease of p-PSD-95 (T19) in the anterior cingulate cortex (ACC) of FMR1^-/- mice. Treating FMR1^-/- mice with 1 Hz repetitive TMS (rTMS) exerted a long lasting effect in improving both the ultrasonic communication and social preference, as well as restoring the levels of Akt/GSK-3β activity and spine density in the FMR1^-/-ACC. Our data, for the first time, demonstrated a beneficial effect of low frequency rTMS (LF-rTMS) on the social function of FMR1^-/- mice and an involvement of Akt/GSK-3β signaling in this process, indicating LF-rTMS as a potential therapeutic strategy for ASD patients.