A groundbreaking study led by UCLA Health has provided the most detailed view yet of the biological mechanisms underlying autism, linking genetic risk of the disorder to cellular and genetic activity across different layers of the brain. Part of the PsychENCODE initiative, the study aims to bridge the gap between genetic risk for psychiatric disorders and causal mechanisms at the molecular level. Led by Dr. Daniel Geschwind, the study on autism builds on years of research focusing on genes that increase susceptibility to autism and identifying molecular changes in the brains of individuals with autism. However, the driving forces behind these changes and their relationship to genetic susceptibility at the cellular and circuit level have remained unclear.
Traditionally, gene profiling for autism spectrum disorder has been limited to using bulk tissue from post-mortem brains of autistic individuals, which provides limited information about differences in brain layers, circuits, and cell types. Geschwind’s study utilized single-cell assays to isolate over 800,000 nuclei from post-mortem brain tissue of individuals with and without autism spectrum disorder. This technique allowed the researchers to identify major cortical cell types affected in autism, including neurons and glial cells. The study found profound changes in neurons connecting the two hemispheres and a group of interneurons important for brain circuit maturation.
A key aspect of the study was the identification of specific transcription factor networks that drive the observed changes in cell subtypes affected by autism. These transcription factors were enriched in known autism risk genes and influenced differential gene expression across specific cell subtypes, linking changes in the brain directly to genetic causes of autism spectrum disorder. By understanding these complex molecular mechanisms, researchers hope to develop new therapeutics to treat autism and other psychiatric disorders. The study provides a refined framework for understanding the molecular changes in the brains of individuals with autism, shedding light on potential causal mechanisms of the disease.
By utilizing cutting-edge single-cell assays, Geschwind and his team were able to identify the major cortical cell types affected by autism spectrum disorder, including neurons and glial cells. The study found significant changes in neurons connecting different brain regions and a group of interneurons crucial for brain circuit maturation. Additionally, the study identified specific transcription factor networks driving these changes, linking them to known autism risk genes. These findings provide insight into potential causal mechanisms of autism and other psychiatric disorders, laying the groundwork for the development of new therapeutics.
The study’s findings offer a comprehensive understanding of the molecular changes that occur in the brains of individuals with autism spectrum disorder, highlighting which cell types are affected and how they relate to brain circuits. The researchers suggest that the observed changes are downstream of known genetic causes of autism, providing valuable information for potential therapeutic interventions. Through the identification of specific transcription factor networks driving these changes, the study offers a more precise framework for understanding the complex biological mechanisms of autism and other psychiatric disorders. The study aims to provide a foundation for developing targeted therapeutic approaches to treat autism and improve outcomes for individuals affected by the disorder.