Non-neuronal mechanisms in autism spectrum disorder (ASD): Microglia and astrocytes at the crossroads with neurons

Autism spectrum disorder (ASD) is a group of complex neurodevelopmental conditions characterized by persistent deficits in social interaction, communication, and repetitive behavior. Although the etiology of ASD has traditionally been linked to neuronal dysfunctions, emerging evidence highlights the significance of non-neuronal cells, particularly microglia and astrocytes, in the pathophysiology of ASD. Although both glial cell types exhibit diverse functional states, microglia are primarily associated with eliminating unused neurons and synapses during early brain development, whereas astrocytes in the tripartite synapse mainly support synapse formation and actively regulate excitatory and inhibitory neurotransmission. Together, microglia and astrocytes complement each other in shaping a dynamic excitatory/inhibitory (E/I) network in the developing brain. Abnormal glial function during critical neurodevelopmental periods is emerging as a significant, and possibly even a leading factor in the E/I imbalance underlying ASD. In this review we highlight recent findings on how microglia and astrocytes contribute to E/I imbalance and other neuronal dysfunctions in ASD, particularly during the vulnerable prenatal period. GABAergic transmission, with a shift in the polarity of GABA action early in development, represents a particularly vulnerable target for aberrant modulation by glia. Recent transcriptomic and multi-omics studies show that signaling pathways thought to be neuron-specific can also be activated in glia at distinct developmental time points, shaping their unique contributions to ASD. This growing knowledge opens new perspectives for using glia-targeted therapeutic approaches for mitigating debilitating aspects of ASD.