Cell Type-Specific Molecular Changes in Autism Spectrum Disorder

Post by Stephanie Williams

What's the science?

Identifying molecular differences that distinguish the brains of individuals diagnosed with autism spectrum disorders (ASD) from non-autistic brains is important for understanding how the brain develops and functions differently in autism. This week in Science, Velmeshev, Kriegstein and colleagues analyzed the transcriptomes of single cells to identify cell-type-specific molecular changes in ASD.

How did they do it?                                            

The authors analyzed the transcriptomes of neural and glial cells from post mortem brain tissue of children and young adults (aged 4 to 22) diagnosed with autism (N=15) and healthy controls (N=16). The authors used single nucleus RNA sequencing (snRNA-seq) to analyze the transcriptomes of single cells in tissue samples from prefrontal cortex and anterior cingulate cortex, two areas known to be affected by ASD. The snRNA-seq technique allowed the authors to analyze the molecular profile of individual cells. Some patients in the ASD cohort had comorbid sporadic epilepsy, which allowed the authors to create an additional age matched group of controls to compare with this group for further analysis. They performed this analysis to tease apart the differences between epilepsy-related molecular changes and ASD-specific molecular changes. The authors then used data from structured interviews to test whether their cell-type specific findings were related to symptom severity.


What did they find?

The authors identified changes in 17 cell types, and found dysregulated development and signaling of upper layer cortical neurons along with activated astrocytes in the ASD group. The genes that the authors found to be most differentially expressed were in layer 2/3 excitatory neurons and vasoactive intestinal polypeptide-expressing interneurons - specifically, genes responsible for synaptic and neurodevelopment. In non-neuronal cells, the top genes differentially expressed were up-regulated in protoplasmic astrocytes and microglia. The authors found that ASD samples contained more protoplasmic astrocytes. Changes in layer 2/3 neurons and microglia were correlated with symptom severity. This correlation suggests that the molecular changes the authors find in the upper layer cortical neurons are responsible for the behavioral symptoms observed in ASD. Analysis of differences between patients who had comorbid ASD and epilepsy with healthy controls revealed changes in L5/6 corticofugal projection neurons and parvalbumin neurons, confirming that the molecular changes observed in the ASD sample were related to ASD pathogenesis and not seizure activity.

What's the impact?

The authors provide a detailed account of specific cell types that contribute to neural pathways affected in the brains of individuals with ASD. Broadly, the authors replicate and extend previous observations about circuit level dysfunction in ASD. Previous work had shown that there was convergence of ASD on specific cell types during development, and the authors extended this finding by showing that there are also convergent transcriptional changes in adult ASD patients. The convergence of the observed molecular changes in the ASD group onto specific cell types in adults has far-reaching implications as it confirms that there may be a common set of targets for therapeutic treatments.


Velmeshev, et al. Single-Cell genomics identifies cell type-specific molecular changes in autism. Science (2019). Access the original scientific publication here.

The authors’ data can be viewed interactively here