Reduced exosomal miR-215-5p activates the NEAT1/MAPK1/p-CRMP2 pathway and contributes to social dysfunction in a VPA-induced autism model

Autism is a prevalent neurodevelopmental disorder characterized by social deficits. Environmental factors, such as prenatal exposure to valproic acid (VPA), are major risk factors for the development of autism in offspring. Environmental epigenetics investigates how environmental factors influence gene expression and function. Exosomal miRNAs carry epigenetic information, but their role in autism remains unknown. Here, we found that prenatal VPA exposure reduced the majority of exosomal miRNA expressions in male newborn amygdala tissue, with exosomal miR-215-5p showing the highest decline. Reduced exosomal miR-215-5p increased neuronal lncRNA NEAT1 expression. Overexpressed neuronal NEAT1 increased the recruitment of the HSP90AB1-MAPK1-CRMP2 complex, which elevated phosphorylated CRMP2 (p-CRMP2) levels. Enhanced p-CRMP2 acted as an “eat me” signal to microglia, resulting in excessive synaptic pruning and aberrant synaptic maturation. Increasing neuronal p-CRMP2 levels via phosphorylation virus T514E or overexpression of MAPK1 promoted microglial synaptic pruning, leading to synaptic defects and social dysfunction. Furthermore, NEAT1 silencing or MAPK1 inhibition reversed the elevated p-CRMP2 levels in VPA-exposed offspring, hence preventing excessive synaptic pruning and social dysfunction. These findings suggested that prenatal VPA exposure reduced exosomal miR-215-5p and activated NEAT1/MAPK1/p-CRMP2 pathway, which resulted in abnormal synaptic development and social interaction disorders.