Remimazolam Ameliorates Autistic‐Like Behaviors via Suppression of Ferroptosis in VTA Dopaminergic Neurons in a Mouse Model of ASD

ABSTRACT Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by social dysfunction and stereotypic behavior, with the neuronal excitation/inhibition (E/I) imbalance as an underlying mechanism. The ultra‐short‐acting GABA‐A receptor agonist remimazolam has elicited unexpected long‐term improvements in agitation and cognition, suggesting a potential role in modulating the E/I imbalance. This study investigates the efficacy and mechanisms of remimazolam on ASD in a valproate (VPA)‐induced model. Intraperitoneal administration of remimazolam significantly ameliorates autistic‐like behaviors, with comparable effects caused by targeted injection of remimazolam into the ventral tegmental area (VTA). Chemogenetic inhibition of VTA dopaminergic neurons in VPA‐exposed mice reverses the therapeutic effects of remimazolam. Conversely, remimazolam also ameliorate the autistic‐like behaviors induced by chemogenetic inhibition. Remimazolam confers protection against VPA‐induced injury to VTA dopaminergic neurons both in vivo and in vitro by inhibiting ferroptosis, as evidenced by the reversal of its key hallmarks: mitochondrial damage, iron overload and lipid peroxidation. Furthermore, ferroptosis agonists reverse the therapeutic effect of remimazolam and ferroptosis inhibitors alleviate the autistic‐like behaviors. This study has demonstrated that remimazolam produces sustained alleviation of autistic‐like behaviors by inhibiting ferroptosis, indicating that ferroptosis may be a critical mechanism to its protection of VTA dopaminergic neurons and resultant behavioral improvement.