Lateral Habenula 5-HT₂A Receptors Mediate Social Deficits in a Valproic Acid-Induced Rodent Model of Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is characterized by social deficits, yet underlying neural mechanisms remain poorly understood. Using a valproic acid (VPA)-induced rodent model of ASD, we demonstrate that hyperactivity of lateral habenula (LHb) neurons, driven by upregulated 5-HT₂A receptors, mediates social impairments. VPA-exposed rats showed significant reductions in sociability, increased anxiety-like behaviors, and elevated repetitive actions. These behavioral changes coincided with enhanced LHb neuronal activity, including increased c-Fos expression and spontaneous firing rates. Transcriptomic and molecular analyses revealed upregulation of 5-HT₂A receptors in the LHb, while electrophysiology confirmed that 5-HT₂A activation augmented neuronal excitability through increased sEPSC frequency/amplitude and firing rates. Crucially, causal validation demonstrated that overexpressing 5-HT₂A receptors in wild-type rats induced ASD-like social deficits, whereas receptor knockdown in VPA-exposed rats reversed sociability impairments. Ablation of LHb neurons similarly rescued social behavior, confirming pathological LHb hyperactivity. Our findings identify LHb 5-HT₂A receptor-mediated hyperexcitability as a novel mechanism driving social dysfunction in ASD. Targeted suppression of this pathway may offer therapeutic strategies for core symptoms.