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

Translational Psychiatry ARTICLE www.nature.com/tp OPEN Treatment with perampanel alleviates depression-like behavior in mice via modulating GluN2B expression to improve excitatory synaptic transmission Jin-Ming Liu Weibin Wu 1,4 3✉ , Yan-Lin Zhang2,4, Fang Guo1,4, Bin-Wu Li ✉ and Xiong Cao 1 1,4 , Hu Chen1, Yuye Mo2, Jiangwei Kong2, Xiaohui Tan 2✉ , 1234567890();,: © The Author(s) 2026 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. Translational Psychiatry (2026)16:90 ; https://doi.org/10.1038/s41398-026-03874-1 INTRODUCTION Major depressive disorder (MDD) is one of the most prevalent mental health disorders worldwide, resulting in a significant disease burden [1, 2]. Most of the antidepressants commonly used in clinical practice are selective serotonin reuptake inhibitors (SSRIs), which tend to be slow-acting and have a low efficacy rate. They are also prone to relapse [3–7]. However, since esketamine was launched in the United States in 2019, numerous clinical studies have confirmed that ketamine has a rapid and effective antidepressant effect in patients with depression. This is undoubtedly a revolutionary development in the treatment of MDD [8–10]. However, ketamine still carries the risk of addiction and hallucinations [11–13]. The antidepressant effects of ketamine are not entirely dependent on NMDAR antagonism; AMPAR also participates in the antidepressant effects of ketamine, particularly through increased expression of GluA1 in the medial prefrontal cortex (mPFC) [14–19]. This suggests that medications targeting the neural glutamate system may have significant potential in antidepressant treatment. Perampanel is a novel, clinically approved antiepileptic medication and non-competitive antagonist of neuronal AMPA receptors [20–22]. Epilepsy with depression occurs in a high percentage of patients in the clinic [23]. Previous studies have shown that, GluA1 protein expression decreased in brain tissue after administration of perampanel to epileptic mice [24]. AMPAR-mediated postsynaptic membrane depolarization is a prerequisite for NMDAR channel opening, which means that AMPAR inhibition can indirectly inhibit NMDAR [17, 25–28]. However, it remains unclear whether perampanel exerts depression-related effects through its action on the neuronal glutamate system. Here, we investigated the role of interactions between AMPA receptors and NMDA receptor subunits in modulating the function of neuronal excitatory synaptic transmission in the glutamate system, and their involvement in the antidepressant effects induced by perampanel. Our comprehensive approach combined behavioral assessment, molecular biology and electrophysiological functional analysis with adenovirus-mediated intervention targeting NMDAR subunit expression. Our results show that interactions between glutamate receptors contribute to the antidepressant properties of perampanel. Therefore, our data may provide new insights for the accurate treatment of patients with epilepsy comorbid with depression using perampanel. 1 Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, P.R. China. 2Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou 510515, P.R. China. 3Department of Psychiatry, The third people’s Hospital of Foshan, Foshan 528000, P.R. China. 4These authors contributed equally: Jin-Ming Liu, Yan-Lin Zhang, Fang Guo, Bin-Wu Li. ✉email: ; ; Received: 21 July 2025 Revised: 17 December 2025 Accepted: 28 January 2026 J.-M. Liu et al. 2 MATERIALS AND METHODS Mice C57BL/6 J mice or CD1 mice were housed in an EVC cage at 22 ± 1 °C, humidity 40% under standard laboratory conditions with a 12 h light/dark cycle and with free access to food and water. C57BL/6 J mice (aged 8 weeks) were obtained from the Southern Medical University Animal Center (Guangzhou, China). The adult male CD1 mice (CD-1®(ICR) Mice, NO. VM0011) (older than 5 months of age) were purchased from Charles River Laboratories (Beijing). Before the behavioral tests, the C57BL/6 J mice were handled every day for 3 days and double-blind behavioral experiments were performed. All of the experiments were conducted in accordance with the Regulations for the Administration of Affairs Concerning Experimental Animals (China) and were approved by the Southern Medical University Animal Ethics Committee (NO. 2016104). Drug injection Perampanel was dissolved in a vehicle of 1% DMSO in saline and administered via intraperitoneal (i.p.) injection at a dose of 0.5 mg/kg. The injection volume was standardized at 10 mL/kg of body weight. Mice in the control group received an i.p. injection of the vehicle solution only. Behavioral studies Chronic social defeat stress. For the Chronic social defeat stress (CSDS) protocol, adult male CD1 mice (>5 months) were purchased from Charles River Laboratories (Beijing). Experimental C57BL/6 J intruder mice were exposed to CD1 aggressor mice for 10 min. After the 10 min social defeat experiment, the CD1 mice and the C57BL/6 J intruder mice were housed in the same cage but separated by partitions for the remainder of the day. The procedure was repeated for 10 consecutive (...truncated)