Involvement of serotonin receptor 7 in synaptic dysfunctions in a mouse model of autism spectrum disorder

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social interaction and communication, repetitive behaviors, and altered brain plasticity. Emerging evidence indicates that impairment in the serotonergic system, particularly involving serotonin receptor 7 (5-HT₇ receptor), plays a crucial role in ASD pathophysiology. In this study, we investigated the synaptic alterations in the brain of juvenile and adult BTBR T + Itpr3tf/J (BTBR) mice, a well-established ASD model, emphasizing the pivotal role of 5-HT₇ receptor in regulating synaptic morphology and functions. Our analyses revealed a significant alteration of pre- and post-synaptic proteins expression, impaired synaptic protein synthesis, and abnormal dendritic spine morphology in the brain cortex of BTBR mice. These synaptic deficits were accompanied by a reduction in 5-HT₇ receptor expression in brain cortex synaptosomes of BTBR mice, underscoring the importance of 5-HT₇ receptor in maintaining synaptic homeostasis. Remarkably, pharmacological activation of 5-HT₇ receptor with the selective agonist LP-211 restored synaptic protein synthesis and ameliorated dendritic spine abnormalities in brain cortex of BTBR mice. Altogether, our findings provide new insights into the molecular underpinnings of ASD, suggesting that targeting the 5-HT₇ receptor is a promising therapeutic approach to address synaptic dysfunctions in neurodevelopmental disorders.