Enriched expression of genes associated with autism spectrum disorders in human inhibitory neurons

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 enriched gene expression in neurons, especially in inhibitory neurons. ASD candidates were also more likely to be the hubs of the co-expressed 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 also 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. Furthermore, the downstream targets of several ASD candidates, such as CHD8, EHMT1 and SATB2, also displayed enriched expression in inhibitory neurons. Taken together, our analysis of single cell transcriptomic data suggest that inhibitory neurons may be the 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.

Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits

“…Combined, these findings suggest a common pathophysiological mechanism in these neurological disorders that starts with GABA impairment and leads to social deficits. However, despite past evidence of abnormal GABA signaling in ASD (Ben-Ari et al, 2012;Cellot and Cherubini, 2014) and indications that cortical inhibitory neurons exhibit enrichment in ASD risk gene expression (Wang et al, 2018), it has remained unclear how alterations in GABA and E/I balance occur in these disorders.…”

Reciprocal control of translation and transcription in autism spectrum disorder

“…Given the extremely complex genetic landscape of ASD, it has been proposed that mutations in these different clusters of genes interfere with interconnected downstream signaling pathways and circuitry in a cell type‐specific manner, resulting in ASD pathophysiology (Santini & Klann, 2014; de la Torre‐Ubieta et al, 2016; Mullins et al, 2016; Wang et al, 2018). The identification of a cluster of genes encoding for transcripts involved in different phases of mRNA translation (Darnell et al, 2011; Santoro et al, 2012) supports one of the unifying theories on ASD according to which dysregulation of translational control represents a common endpoint of familial and sporadic ASD‐associated signaling pathways (Kelleher & Bear, 2008; Darnell & Klann, 2013; Santini & Klann, 2014).…”