Abstract
Autism spectrum disorder (ASD) is a heterogenous group of neurodevelopmental disorders characterized by social communication deficits and repetitive behaviors. While our current understanding the mechanisms underlying ASD is growing, effective treatment options are still underdevelopment. Extracellular vesicles derived from the probiotic Lactobacillus paracasei (LpEV) exhibit neuroprotective effects in vitro and in vivo models. This study investigates whether LpEV can improve core symptoms in genetic ASD models that represent accumulated developmental deficits. Mice lacking dopamine receptor-2 (Drd2 KO mice) exhibit social behavior deficits and excessive grooming. LpEV treatment in Drd2 KO mice significantly improves these autistic-like behaviors, suggesting LpEV's ability to potentially mitigate the persistent dysregulated signaling pathways in these mice. RNA sequencing followed by gene ontology enrichment analysis of LpEV-treated Drd2 KO mice reveals distinct groups of genes with expression reversed by LpEV. Notably, a high proportion of these genes overlap significantly with known ASD genes in the SFARI database, strengthening the potential of LpEV to target relevant pathways in ASD. Further investigation identifies Oxytocin and Oxytocin receptor (Oxtr) as potential therapeutic targets. LpEV treatment significantly improves autistic-like behaviors in mice with reduced Oxtr function (Oxtr heterozygous mice). LpEV treatment also improves autistic-like behaviors in mice lacking adenylyl cyclase-5, suggesting its potential to target ASD through broader mechanisms beyond a single pathway. These results highlight the therapeutic potential of LpEV in reversing the accumulated dysregulated signaling pathways critical for ASD core symptoms and improving autistic-like behaviors.