Characterization of Cell-cell Communication in Autistic Brains with Single Cell Transcriptomes

Abstract

Autism spectrum disorder is a neurodevelopmental disorder, affecting 1-2% of children. Studies have revealed genetic and cellular abnormalities in the brains of affected individuals, leading to both regional and distal cell communication deficits. Recent application of single cell technologies, especially single cell transcriptomics, has significantly expanded our understanding of brain cell heterogeneity and further demonstrated that multiple cell types and brain layers or regions are perturbed in autism. The underlying high-dimensional single cell data provides opportunities for multi-level computational analysis that collectively can better deconvolute the molecular and cellular events altered in autism. Here, we apply advanced computation and pattern recognition approaches on single cell RNA-seq data to infer and compare inter-cell-type signaling communications in autism brains and controls. Our results indicate that at a global level there are cell-cell communication differences in autism in comparison to controls, largely involving neurons as both signaling senders and receivers, but glia also contribute to the communication disruption. Although the magnitude of change is moderate, we find that excitatory and inhibitor neurons are involved in multiple intercellular signaling that exhibit increased strengths in autism, such as NRXN and CNTN signaling. Not all genes in the intercellular signaling pathways are differentially expressed, but genes in the pathways are enriched for axon guidance, synapse organization, neuron migration, and other critical cellular functions. Furthermore, those genes are highly connected to and enriched for genes previously associated with autism risks. Overall, our proof-of-principle computational study using single cell data uncovers key intercellular signaling pathways that are potentially disrupted in the autism brains, suggesting that more studies examining cross-cell type affects can be valuable for understanding autism pathogenesis.

Context-aware deconvolution of cell-cell communication with Tensor-cell2cell

“…We observed that each factor was associated with different biological functions including axon guidance, cell adhesion, extracellular-matrix-receptor interaction, ERBB signaling, MAPK signaling, among others (Figure 5b). Dysregulation of axon guidance, synaptic processes and MAPK pathway have been previously linked to ASD from differential analysis 55,58 , supporting our observations. Moreover, our results extend to other roles associated with extracellular matrix, focal adhesion of cells, regulation of actin cytoskeleton, and signaling through ErbB receptors, which involves Akt, PI3K, and mTOR pathways, as well as regulation of cell proliferation, migration, motility, differentiation, and apoptosis 59 .…”

“…In our ASD case-study (Figure 5), such analyses included GSEA, clustering, visualization and statistical comparison of factors, and factor-specific analysis of sender-receiver communication networks (Supplementary Figure S9). In the ASD case-study, we found dysregulated CCC directly distinguished ASD patients from controls and was linked with a downregulation of axon guidance, cell adhesion, synaptic processes, and ERBB signaling in cortical neurons and interneurons (Figures 5a,b), consistent with previous evidence 55,58,63,64 . Moveover, accounting for the combinatorial relationship of samples across factors demonstrated additional complex relationships of CCC dysregulation (Figure 5d).…”

Expression and structural analysis of human neuroligin 2 and neuroligin 3 implicated in autism spectrum disorders

“…The development of ASD is closely related with neuronneuron communications (64). Synaptic adhesion molecules mediate the communications between presynaptic and postsynaptic neurons and play critical roles in synapse development and plasticity (65).…”

Systematic Bibliometric and Visualized Analysis of Research Hotspots and Trends on Autism Spectrum Disorder Neuroimaging

“…ASD neuroimaging research examines the brain from a variety of perspectives including brain structure, functional connections, and neurometabolic [8][9][10]. Structural magnetic resonance imaging (sMRI) is a technique for examining the anatomical structure of the brain.…”