Selective magnetic stimulation downregulates the GABAA receptor ε subunit in the left prelimbic cortex to alleviate schizophrenia-like behaviors in mice

Schizophrenia (SCZ) is a prevalent and disabling mental disorder. Clinically, its complex symptoms, including negative symptoms and cognitive impairment, can be alleviated using electromagnetic techniques such as repetitive transcranial magnetic stimulation (rTMS). To investigate the neural mechanisms of magnetic stimulation and identify selective therapeutic targets, we employed combined magnetic stimulation system treatment (c-MSST). Targeting the left prelimbic cortex (PrL) of mice with c-MSST reversed the SCZ-like behaviors and synaptic abnormalities induced by MK-801 injection and normalized the regional increase in gamma-aminobutyric acid type A receptor subunit epsilon (GABRE) expression. Specific Gabre knockdown in the left PrL ameliorated MK-801-induced SCZ-like behaviors. Importantly, Gabre conditional knock-in mice exhibited SCZ-like behaviors and synaptic plasticity deficits, both of which were reversed by c-MSST. We further demonstrated that the ability of c-MSST to reduce GABRE protein expression may be related to p62/SQSTM1-mediated sequestration of GABARAP family. Our study improves the understanding of the therapeutic mechanisms of magnetic techniques and suggests that Gabre and related molecular circuits are promising targets for SCZ treatment.