5-HT7 RECEPTOR UPREGULATION AND LP-211 TREATMENT REVERSE ELECTROPHYSIOLOGICAL AND BEHAVIORAL DEFICITS IN A VALPROIC ACID–INDUCED RAT MODEL OF AUTISM

Autism spectrum disorder (ASD) is associated with widespread alterations in serotonergic neurotransmission, including disrupted serotonin (5-HT) levels, abnormal transporter function, and altered expression of specific 5-HT receptor subtypes. Despite the recognized involvement of the 5-HT system in ASD, the functional contribution of 5-HT7 receptors (5-HT7Rs) to ASD-related neurophysiology remains insufficiently understood. Prenatal exposure to valproic acid (VPA) is a well-established model for studying ASD-like phenotypes in rodents. In this study, we investigated the expression and functional role of 5-HT7Rs in the hippocampal CA1 region of VPA-exposed rats. We assessed whether chronic activation of 5-HT7Rs with the selective agonist LP-211 could restore cellular and behavioral abnormalities.
Our findings demonstrate a significant upregulation of 5-HT7R expression in the CA1 subregion following prenatal VPA exposure. Patch-clamp recordings revealed pronounced electrophysiological impairments in hippocampal pyramidal neurons of autistic-like rats, including disrupted synaptic plasticity. Chronic LP-211 treatment effectively reversed these deficits, restoring intrinsic excitability and synaptic responsiveness. Behavioral testing further showed that LP-211 administration improved motor coordination, enhanced novel object recognition memory, and reduced stereotypic behaviors in VPA-exposed offspring.
These results indicate that 5-HT7R dysregulation contributes to hippocampal dysfunction in ASD and suggest that pharmacological activation of 5-HT7Rs may represent a promising therapeutic strategy. Our findings highlight the potential of 5-HT7R-targeting compounds, such as LP-211, to ameliorate both electrophysiological and behavioral abnormalities associated with ASD.