The role of astrocytes in autism spectrum disorder and associated syndromes: evidence, animal models, mechanisms, and therapeutic potential

Autism spectrum disorder (ASD) is a neurodevelopmental condition clinically defined by persistent social deficits and restricted, repetitive behavior. Several other neurodevelopmental disorders exhibit these core clinical features of ASD and are therefore classified as “syndromic ASD”. Although neurons have been the primary research focus on ASD and associated syndromes, accumulating evidence highlights astrocytes as critical contributors to disease mechanisms. Astrocytes are essential for regulating synapse development, neurotransmitter balance, and neuroinflammation in the brain. In this review, we integrate evidence from studies in human tissues, patient-derived induced pluripotent stem cells and organoids, and animal models to establish a robust link between astrocytic dysfunction and ASD and associated syndromes. By systematically examining key astrocytic functions, we elucidate mechanistic pathways through which astrocytic dysregulation contributes to aberrant synaptogenesis, disrupted ion and neurotransmitter homeostasis, maladaptive neuroinflammatory signaling, and impaired metabolic coupling in ASD and associated syndromes. Finally, we discuss the potential of various astrocyte-targeted interventions, which hold promise for advancing precision medicine approaches to these devastating disorders.