UCLA Health that have been exploring the genetics of autism. The research has revealed a connection between genetic risk and the observed cellular and genetic activity in various parts of the brain. This discovery provides a more comprehensive understanding of the complex biological processes involved in autism. The study is a significant step forward in unraveling the underlying mechanisms of the disorder.The PsychENCODE consortium, organized by the National Institutes of Health, was started in 2015 and is led by Dr. Daniel Geschwind from UCLA. Its goal is to generate maps of gene regulation in various areas of the brain and at different points in brain development. The consortium aims to connect research on the genetic risk factors for psychiatric disorders with the potential underlying molecular mechanisms. This collection of articles from PsychENCODE is a valuable resource for gaining insight into the connection between disease risk and genetic mechanisms.Geschwind stated that “Geschwind’s research on autism, published in the May 24 issue of Science, is part of a larger body of work by his team that has been profiling genes associated with autism spectrum disorder and identifying common molecular changes in the brains of people with autism. However, the underlying causes of these molecular changes and their connection to genetic susceptibility at the cellular and circuit levels in this complex condition are still not well understood.”
He noted that previous gene profiling for autism spectrum disorder has been mostly limited to using bulk techniques, with a few exceptions in smaller studies.The issue with studying brain tissue from individuals with autism after they have passed away is that it does not provide detailed information about the differences in brain layers, circuit levels, and specific cell type pathways associated with autism, as well as the mechanisms for gene regulation. To overcome this challenge, Geschwind utilized single-cell assays, a technique that allows researchers to extract and identify genetic information from the nuclei of individual cells. This approach enables researchers to navigate the complex network of different cell types in the brain. Over 800,000 nuclei were isolated from post-mortem brain tissue.The study included a total of 66 participants ranging in age from 2 to 60. This group consisted of 33 individuals diagnosed with autism spectrum disorder and 30 neurotypical individuals who served as the control group. Among those with autism, five had a specific genetic form known as 15q duplication syndrome. The researchers made sure to match each sample based on age, sex, and cause of death, in order to create a balanced comparison between the cases and controls.
As a result of their study, Geschwind and his team were able to pinpoint the major types of cortical cells that are impacted in autism spectrum disorder. This included both neurons and their support cells, which are referred to as glial cells. The research revealed that the most significant changes were observed in the Neurons are responsible for connecting the two hemispheres of the brain and enabling long-range communication between different brain regions. Additionally, a group of interneurons known as somatostatin interneurons play a key role in the maturation and refinement of brain circuits.
This study focused on identifying specific transcription factor networks, which are the complex interactions that control when a gene is activated or suppressed. Interestingly, these networks were found to be enriched in genes associated with autism spectrum disorder, and they had a significant impact on differential gene expression across various brain regions.Specialized cell subtypes have been identified for the first time, potentially linking changes in the brain in ASD directly to the genetic causes. Understanding these complex molecular mechanisms that underlie autism and other psychiatric disorders could lead to the development of new treatments. According to Geschwind, these findings offer a strong and detailed framework for comprehending the molecular changes in the brains of individuals with ASD, including the specific cell types affected and their relationship to brain circuits. The changes observed are believed to be downstream of known genetic causes of autism.The study focuses on ASD and aims to uncover underlying mechanisms of the disease.”
