UT Southwestern Medical Center researchers have uncovered a pivotal role of a gene linked to autism spectrum disorder (ASD) in guiding cells within the brain's hippocampus towards their distinct identities, as reported in a recent study published in Science Advances. The findings carry potential implications for the development of novel therapies for ASD, a prevalent neurodevelopmental disorder affecting approximately 1 in 36 children in the United States.
Senior author Maria Chahrour, Ph.D., Associate Professor of Neuroscience and Psychiatry at UT Southwestern, highlighted the significance of this study as one of the few providing a mechanistic understanding of ASD. With about 90% heritability suggested by twin studies, emphasizing the role of genetics in ASD, hundreds of associated genes have been identified, but their specific contributions to the disorder remain largely unknown.
In 2020, Dr. Chahrour and her team identified an ASD-associated gene, KDM5A, revealing that mutations in this gene often coincide with ASD, speech impairment, intellectual disability, and other symptoms. While KDM5A is recognized as encoding a chromatin regulator impacting DNA packaging and gene expression, its precise mechanism in ASD was previously elusive.
Examining a mouse model with the eliminated KDM5A gene, the researchers explored cell types in the hippocampus, a region altered in ASD. Utilizing single-nuclei RNA sequencing, they sequenced over 105,000 nuclei to compare cell type populations in mice with and without KDM5A. The analysis unveiled notable differences in several excitatory and inhibitory neuron subtypes, indicating KDM5A's significant role in determining cell identity during development.
Further scrutiny of KDM5A knockout mice hippocampi revealed cells appearing more mature, with increased and elongated branching cells, particularly in the CA1 region crucial for social memory storage. Changes in cell types may lead to imbalances in excitation and inhibition, potentially damaging hippocampal circuits and contributing to ASD symptoms.
Dr. Chahrour emphasized that these findings align with her lab's mission: to comprehend the molecular mechanisms underlying ASD and related neurodevelopmental conditions. This research sheds light on the intricate interplay between genetics and cellular development, providing a stepping stone for potential therapeutic interventions targeting the identified pathways associated with ASD.
Source: UT Southwestern Medical Center