Treatment with perampanel alleviates depression-like behavior in mice via modulating GluN2B expression to improve excitatory synaptic transmission.

Antidepressants that target the glutamatergic system, such as ketamine, have shown promising results. However, the contribution of other potential medications targeting the glutamate system to depression is unclear. Our research found that perampanel can exert a rapid and long-lasting antidepressant effect to improve the behavior of chronic social defeat stress (CSDS) depression susceptible mice. In mechanism, perampanel reduce the abnormal increase in the expression of the NMDA receptor subunit GluN2B (Grin2b) in the medial prefrontal cortex (mPFC), further increase the expression of the AMPA receptor subunit GluA1 (Gria1), and improve the functional impairment of excitatory synaptic transmission in the mPFC in depression susceptible mice. Meanwhile, Naïve mice (non-stressed controls) administered perampanel would rapidly exhibit depression-like behaviors. This is because perampanel inhibits the function of excitatory synaptic transmission in the mPFC of Naïve mice. Indeed, perampanel shows different effects in depression susceptible mice and Naïve mice. Our research reveals that an FDA-approved perampanel for clinical treatment of epilepsy, has rapid antidepressant potential. This finding may provide more treatment options and precise medication guidance for clinical patients with depression and for those with epilepsy accompanied by depression.