A recent study by researchers at Weill Cornell Medicine suggests that a gene associated with autism spectrum disorders plays a crucial role in early brain development and may impact the formation of both conventional and abnormal nerve connections in the brain.
The research, which was published on November 28 in Neuron, used a combination of cutting-edge genetic experiments in mice and analysis of human brain imaging data to better understand why mutations in a gene called Gabrb3 are associated with an increased risk of developing autism spectrum disorder (ASD) and a related condition called Angelman Syndrome. Both disorders are characterized by irrational behavior and strange reactions to sensory inputs, features that appear to originate, at least in part, in the development of faulty neural connections in the brain.
Dr. Rachel Babij, who participated in the Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-Ph.D. program in the lab of Natalia De Marco Garca, associate professor in the Feil Family Brain and Mind R esearch Institute said that neuronal connections in the brain, and developmental synchronization of neuronal networks, are altered in individuals with autism spectrum disorders.
Inhibitory connections in the brain, which serve to slow down overactive neurons and keep the nervous system running smoothly like traffic cops, are encoded in part by the gene Gabrb3. Gabrb3 appears to have a role in regulating the establishment of synapses in the developing brain.
Babij and her team monitored cellular signaling in the developing brains of both wild-type and Gabrb3-deficient rats. Babij and co-first author Camilo Ferrer, a postdoctoral fellow in the De Marco Garca lab, and others performed preclinical tests showing that mice lacking Gabrb3 are unable to build the typical network of connections between neurons in certain brain area important in sensory processing.
De Marco Garca, the paper’s lead author said that it’s not a systemic problem in which every single neuron will fail to connect, or improperly make contact, their targets; but it’s really a group of cells that are more sensitive to this.
The scientists, working with Dr. Theodore Schwartz’s group at Weill Cornell, demonstrated that the deletion of Gabrb3 led to an increase in functional connections between the two hemispheres of the brain in the genetically engineered mice, as compared to animals with a functional Gabrb3 gene. The genetically altered mice are also extremely touch sensitive. After this gene is deleted, basically what they discover is that these neurons are more receptive to sensory events.
The researchers worked with Dr. Conor Liston’s group at Weill Cornell to analyze human neuroimaging data to better understand the gene’s function. Human GABRB3 gene spatial distribution was shown to be associated with unusual neural connections in individuals with ASD, as determined by the study’s authors. Specifically, De Marco Garca found that the lower the expression of GABRB3 in a certain region of the brain, the greater the likelihood that region will have abnormal nerve connections.
De Marco Garca, while cautioning against making direct comparisons between the preclinical and human data, suggests that both analyses point to a model of neurologic disorders in which alterations in genes like GABRB3 could drive specific changes in neuronal communication patterns, ultimately resulting in abnormal behaviors. Gene interactions can have dramatic effects because they blend the effects of several genes.
When both schizophrenia and autism spectrum disorder include a malfunction of the brain’s inhibitory neurons, what separates the two? Researchers speculate that the mutations affecting particular kinds of neurons may have a role in the etiology of these disorders.
Sources:
Rachel Babij et al. (2022). Gabrb3 is required for the functional integration of pyramidal neuron subtypes in the somatosensory cortex, Neuron. DOI: 10.1016/j.neuron.2022.10.037
https://medicalxpress.com/news/2022-12-autism-linked-gene-nerve.html
