Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD

Abstract

Neuropsychiatric disorders classically lack defining brain pathologies, but recent work has demonstrated dysregulation at the molecular level, characterized by transcriptomic and epigenetic alterations1–3. In autism spectrum disorder (ASD), this molecular pathology involves the upregulation of microglial, astrocyte and neural–immune genes, the downregulation of synaptic genes, and attenuation of gene-expression gradients in cortex1,2,4–6. However, whether these changes are limited to cortical association regions or are more widespread remains unknown. To address this issue, we performed RNA-sequencing analysis of 725 brain samples spanning 11 cortical areas from 112 post-mortem samples from individuals with ASD and neurotypical controls. We find widespread transcriptomic changes across the cortex in ASD, exhibiting an anterior-to-posterior gradient, with the greatest differences in primary visual cortex, coincident with an attenuation of the typical transcriptomic differences between cortical regions. Single-nucleus RNA-sequencing and methylation profiling demonstrate that this robust molecular signature reflects changes in cell-type-specific gene expression, particularly affecting excitatory neurons and glia. Both rare and common ASD-associated genetic variation converge within a downregulated co-expression module involving synaptic signalling, and common variation alone is enriched within a module of upregulated protein chaperone genes. These results highlight widespread molecular changes across the cerebral cortex in ASD, extending beyond association cortex to broadly involve primary sensory regions.

ASD modelling in organoids reveals imbalance of excitatory cortical neuron subtypes during early neurogenesis

“…One interesting point of convergence is that we noted a general decrease in cortical area-specific transcripts in organoids ( Extended Data Fig. 6B ), which is consistent with the flattening of transcriptomic differences across cortical regions found in the adult cortex of ASD individuals 47, 48 . However, since cellular context are drastically different between early development and adulthood and head circumference needs to be also evaluated in adult postmortem data, further meta-analyses are required for a proper comparison.…”

“…On the contrary, marker genes of cortical areas identified in fetal brain 46 were overall prevalently downregulated in both ASD cohorts ( Extended Data Fig. 6B,C ), similarly to what has been described in vivo 47, 48 .…”

“…A general alteration in EN and IN neurogenesis has been proposed in studies of penetrant ASD genes in organoids or of postmortem cortex from ASD individuals 18, 48, 63, 64 . Around half of the genes differentially expressed in transcriptomic studies of adult postmortem ASD brains 48, 64 were also differentially expressed in our study, however the direction of change was typically unrelated. One interesting point of convergence is that we noted a general decrease in cortical area-specific transcripts in organoids ( Extended Data Fig.…”

Brain region-specific changes in neurons and glia and dysregulation of dopamine signaling inGrin2amutant mice

“…In this context, it is interesting that Grin2a +/impacts the PFC much more than heterozygous LoF of the ASD gene Grin2b (Fig. 1F), which is consistent with a recent human brain transcriptomic study showing that ASD has relatively little effect on PFC compared to other neocortical areas (Gandal et al, 2022). Our finding, based on transcriptomics, that Grin2a +/mutants exhibit hypofunction particularly in PFC is intriguing because there is clinical evidence for reduced activity and brain volume in parts of PFC in SCZ by functional neuroimaging (Minzenberg et al, 2009;Pomarol-Clotet et al, 2010).…”

Identifying novel convergent roles of neuronal β-catenin and APC in modulating mRNA translation, plasticity and learning

“…1b), that express Cre recombinase predominantly in forebrain excitatory neurons, starting at late embryonic ages and progressively increasing to complete activation by P21 36 . This is a disease relevant developmental age and cell type for intellectual disabilities and autism based on both mouse and human brain studies [40][41][42][43] .…”