Autism Spectrum Disorders and Purinergic Signaling: A Systematic Review of Emerging Insights from Preclinical Studies

Autism Spectrum Disorders (ASD), are a group of complex neurodevelopmental conditions characterized by deficits in social communication and the presence of restricted, repetitive behaviors. ASD rates are rising alarmingly in the United States and the reason behind this is obscure. Increasing evidence suggests that purinergic signaling, a form of extracellular signaling mediated by purine nucleosides and nucleotides such as adenosine and adenosine triphosphate (ATP), plays a critical role in neurodevelopment and immune function. This systematic review summarizes preclinical studies focusing on the relationship between purinergic signaling pathways and ASD, focusing on molecular, cellular, and behavioral studies. A comprehensive literature search through 2024 was carried out in PubMed, Scopus, and Web of Science databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 23 preclinical studies met our inclusion criteria and were included in the final review. The findings suggest that aberrant purinergic receptor expression, dysregulated ATP/adenosine status and ectonucleotidase level largely contribute to behavioral and synaptic abnormalities, dysregulation in neurotransmission, neuroinflammation and perturbed glial communication in ASD animal models. These insights support the hypothesis that purinergic signaling dysfunction contributes to the etiology and pathophysiology of ASD and represents a promising therapeutic target.