A groundbreaking study led by UCLA Health has provided the most detailed view yet of the biological processes underlying autism, connecting genetic risk factors directly to specific cellular and genetic activities in various brain regions.
This research, part of the National Institutes of Health’s PsychENCODE consortium and spearheaded by neurogeneticist Dr. Daniel Geschwind, marks a significant advance in understanding autism at the molecular level.
Published in the prestigious journal Science, this study is one of nine from the consortium aiming to map gene regulation throughout different brain areas and development stages.
The initiative seeks to connect the dots between genetic risk and the molecular mechanisms potentially causing various psychiatric disorders.
Dr. Geschwind’s research has long focused on profiling genes that heighten autism spectrum disorder (ASD) susceptibility and identifying molecular changes in the brains of individuals with autism.
Despite substantial progress, the specific molecular drivers and their relation to genetic risks at the cellular and circuitry levels of the brain have remained elusive.
Traditionally, autism gene profiling has relied on bulk tissue samples from deceased individuals with autism, which provides limited insights into the nuanced differences across brain layers, cell types, and circuits.
To overcome these limitations, Dr. Geschwind’s team utilized cutting-edge single-cell assays. This technique allows for the extraction and analysis of genetic data from individual cell nuclei, offering a granular view of the brain’s diverse cellular landscape.
The study examined over 800,000 nuclei from post-mortem brain tissues of 66 individuals, ranging from 2 to 60 years old.
This group included 33 people with ASD and 30 neurotypical controls, matched by age, sex, and cause of death. Among the autistic individuals, five had a genetically defined form of autism known as 15q duplication syndrome.
The analysis revealed significant changes in major cortical cell types in individuals with ASD, particularly in neurons that link the brain’s hemispheres and provide long-range connectivity.
Additionally, alterations were found in a type of interneuron known as somatostatin interneurons, which are crucial for the maturation and refinement of brain circuits.
One of the key achievements of this research was identifying specific transcription factor networks—complexes of proteins that regulate gene expression.
These networks were found to be enriched in genes already associated with a high risk of ASD and appeared to drive significant expression changes in particular cell subtypes.
This connection between genetic risk factors and molecular changes in the brain provides new insights into how genetic predispositions can lead to the observed symptoms of ASD.
Dr. Geschwind emphasized the implications of these findings for developing potential new treatments for autism.
“These findings provide a robust and refined framework for understanding the molecular changes that occur in the brains of people with ASD—identifying which cell types are involved and how they relate to brain circuits,” he stated.
“This helps us see that the observed changes are a result of known genetic causes of autism, offering insights into potential causal mechanisms of the disease.”
This pioneering study not only advances our understanding of the intricate molecular dynamics in autism but also opens new avenues for therapeutic intervention, potentially leading to more effective treatments for ASD in the future.
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The research findings can be found in Science.
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