Autism spectrum disorder: the interaction between dopaminergic and cholinergic systems in animal models

Dysregulation of neurotransmitter systems, particularly dopaminergic and cholinergic pathways, is implicated in the pathogenesis of autism spectrum disorder (ASD). ASD is characterized by social communication difficulties and repetitive behaviors, including early-onset motor stereotypies. Investigating neurotransmitter alterations in ASD is challenging, but advances in imaging, postmortem analyses, and animal models have revealed dysfunctions in glutamatergic, gamma-aminobutyric acid (GABA)ergic, dopaminergic, and cholinergic systems. Rodent models, including genetic and environmentally induced paradigms, reliably recapitulate autistic-like motor behavior and provide insight into underlying neural mechanisms. Recent single-cell transcriptomic studies reveal heterogeneity among midbrain dopaminergic neurons, emphasizing their diverse roles in ASD pathology. This review aims to synthesize current knowledge on dopaminergic and cholinergic system alterations in ASD-related brain regions and their contribution to early motor and repetitive behavioral phenotypes. Important questions remain about the long-term effects of pharmacological manipulation of cholinergic and dopaminergic receptors, as most studies focus on acute effects. This also suggests a need to investigate the differentiation of dopaminergic and cholinergic neurons during early brain development. Understanding crosstalk between dopaminergic and cholinergic pathways offers promising potential for elucidating ASD etiology and developing targeted interventions.