Decoding the contribution of dopaminergic genes and pathways to autism spectrum disorder (ASD)

• Clinical and basic studies strongly implicate dopamine (DA) in autism pathogenesis.
• Here we analyze bionetworks of DA-related proteins, and assess their role in ASD.
• Our analyses highlight several ASD-related cellular pathways modulated by central DA.
• They include cellular modulators of DA metabolism/signaling and cytoskeletal proteins.
• DA-related modulators of Ca2+/other mediators’ signaling are also involved in ASD.

Autism spectrum disorder (ASD) is a debilitating brain illness causing social deficits, delayed development and repetitive behaviors. ASD is a heritable neurodevelopmental disorder with poorly understood and complex etiology. The central dopaminergic system is strongly implicated in ASD pathogenesis. Genes encoding various elements of this system (including dopamine receptors, the dopamine transporter or enzymes of synthesis and catabolism) have been linked to ASD. Here, we comprehensively evaluate known molecular interactors of dopaminergic genes, and identify their potential molecular partners within up/down-steam signaling pathways associated with dopamine. These in silico analyses allowed us to construct a map of molecular pathways, regulated by dopamine and involved in ASD. Clustering these pathways reveals groups of genes associated with dopamine metabolism, encoding proteins that control dopamine neurotransmission, cytoskeletal processes, synaptic release, Ca2+ signaling, as well as the adenosine, glutamatergic and gamma-aminobutyric systems. Overall, our analyses emphasize the important role of the dopaminergic system in ASD, and implicate several cellular signaling processes in its pathogenesis.