Abstract
Autism spectrum disorder (ASD) is highly heritable but genetically heterogeneous. The affected neural circuits and cell types remain unclear and may vary at different developmental stages. By analyzing multiple sets of human single cell transcriptome profiles, we found that ASD candidates showed relatively enriched gene expression in neurons, especially in inhibitory neurons. ASD candidates were also more likely to be the hubs of the co-expression gene module that is highly expressed in inhibitory neurons, a feature not detected for excitatory neurons. In addition, we found that upregulated genes in multiple ASD cortex samples were enriched with genes highly expressed in inhibitory neurons, suggesting a potential increase of inhibitory neurons and an imbalance in the ratio between excitatory and inhibitory neurons in ASD brains. Furthermore, the downstream targets of several ASD candidates, such as CHD8, EHMT1 and SATB2, also displayed enriched expression in inhibitory neurons. Taken together, our analyses of single cell transcriptomic data suggest that inhibitory neurons may be a major neuron subtype affected by the disruption of ASD gene networks, providing single cell functional evidence to support the excitatory/inhibitory (E/I) imbalance hypothesis.
Highlights
Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders characterized by persistent deficits in social communication/interaction and restricted, repetitive patterns of behaviors, interests or activities (DSM-5)[1]
The enrichment of inhibitory neuronal expression among ASD candidate genes provides molecular support for the finding that deficits in inhibitory neuronal function occurs in some syndromes with autism-associated behaviors, such as individuals with ARX mutations[70,71], Dravet syndrome caused by loss-of-function mutations in SCN1A72, and Tuberous Sclerosis caused by mutations in TSC1/273,74
A relative excess of inhibitory neuronal activity has been observed in mouse models of Rett Syndrome[76], and mice with a targeted Mecp[2] deletion restricted to GABAergic inhibitory neurons recapitulates most of the ASD-like features observed in animal models[77], while restoring Mecp[2] expression reverses some of the phenotypical defects[78,79]
Summary
Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders characterized by persistent deficits in social communication/interaction and restricted, repetitive patterns of behaviors, interests or activities (DSM-5)[1]. And twin studies have found that ASD is highly heritable[4,5], but the genetic risk factors for ASD are highly heterogeneous and up to one thousand genes are estimated to be involved, with no single gene accounting for >1–2% of the cases[6]. These ASD candidate genes converge on several molecular and cellular pathways, such as synaptic function, Wnt-signal.
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