Spontaneous Neuronal Activity in Autism Spectrum Disorder: Insights from Human and Animal Studies

Developmental spontaneous neuronal activity (SNA) plays an instrumental role in the generation of precise brain circuits. Spontaneous activity patterns guide neuronal differentiation, synaptic refinement, and circuit formation; consequently, perturbations in these activity patterns can profoundly influence brain network organization. Growing evidence suggests that mutations in autism-associated genes lead to alterations of the SNA pattern during early brain development, thereby giving rise to the behavioral features of autism spectrum disorder (ASD). This review integrates findings from neuroimaging studies, which reveal widespread alterations in neuronal excitability in individuals with ASD. Regional homogeneity and functional connectivity analyses consistently demonstrate region-specific abnormalities, including hyperactivity in higher-order cortical regions, hypoactivity in sensorimotor areas, and disrupted long-range connectivity. These functional alterations are closely linked to the underlying molecular and cellular mechanisms such as excitation-inhibition (E/I) imbalance, impaired GABAergic signaling, glutamatergic dysregulation, and abnormalities in calcium-dependent signaling pathways. Identification of activity-based biomarkers, together with advanced neuroimaging techniques and computational and machine learning (ML) approaches, may facilitate early diagnosis of ASD. Understanding the origin and consequences of alterations in SNA provides a unifying framework for identifying novel targets for designing pharmacological intervention strategies.