A mutation in a gene called Syngap1 is known to disrupt early brain development, resulting in various severe cognitive and behavioral disabilities. Research led by 2009 NARSAD Young Investigator Grantee Gavin Rumbaugh, Ph.D., has pinpointed how disability arises by identifying the specific type of developing brain cells—forebrain excitatory neurons—affected by the mutation. The damage to these developing cells creates an ongoing dysfunction that perpetuates disability into adulthood. The new finding opens the way to potential prenatal diagnosis and targeted treatment of Syngap1-induced abnormalities before permanent dysfunction is set into motion.
The study paper, published online on June 18th in the journal Neuron, noted that Syngap1 is “among the most commonly mutated genes in cases of sporadic intellectual disability. Affected individuals also have a high incidence of childhood seizures and autism spectrum disorder.” Syngap1 mutation has been linked as well to epileptic encephalopathy, a devastating and often fatal form of childhood epilepsy.
The specific excitatory neurons at play are called glutamatergic neurons. In studies with mice models, the researchers found that the problems caused by Syngap1 mutations were restricted to glutamatergic neurons in the forebrain and that removing the Syngap1 mutation from these cells prevented cognitive abnormalities from developing.
"We found a sensitive cell type that is both necessary and sufficient to account for the bulk of the behavioral problems resulting from this mutation," said Dr. Rumbaugh, an Associate Professor in the Department of Neuroscience at The Scripps Research Institute, Florida campus, who worked with a multi-institutional team that included 2012 NARSAD Young Investigator Grantee Xiangmin Xu, Ph.D., of the University of California, Irvine. “Because we found the root biological cause of this genetic brain disorder,” he explained, “we can now shift our research toward developing tailor-made therapies for people affected by Syngap1 mutations.”