Novel Techniques Unveil How Altered Genes Affect Pathways in the Brain

Autism falls on a spectrum, meaning its symptoms show up in a wide variety of ways around its hallmark differences in social and communication abilities. Scientists understand a great deal about how these develop within biological systems and have linked about 100 genes to autism. In fact, about 20% of autism diagnoses are the result of identifiable genetic alterations. Now, Duke Center for Autism and Brain Development investigators including Scott Soderling, Ph.D., a cell biologist, neuropsychopharmacologist William Wetsel, Ph.D., and clinical geneticist Yong-hui Jiang, M.D., Ph.D., are studying how a single genetic variant plays a major role in social and communication differences for those on the spectrum.

"We study how signaling pathways are organized and how a single genetic mutation, such as a mutation in a sodium channel gene (SCN2A), can lead to neurodevelopmental conditions, including autism,” said Soderling, the George Barth Geller Distinguished Professor for Research in Molecular Biology at Duke University. “What we are learning could set the stage to find more targeted treatments that could improve quality of life for autistic individuals."

The team is using animal genetic models and novel genome engineering techniques to understand how an SCN2A genetic mutation in humans influences molecular brain functions and alters pathways in the brain, leading to differences in social behavior, communication, and other behaviors associated with autism. The multi-year investigation could reveal novel insights into how a small, significant change in the SCN2A gene influences brain function.

Using a gene editing technique called CRISPR (clustered regularly interspaced short palindromic repeats), the team created genetically modified animal models that carry the same Scn2a modification in mice that appears in autism in humans. Now, the researchers are assessing the behavior of the mice with modified genes, using tests designed to assess motor performance, learning and memory processes, anxiety, communication, social behavior, and repetitive behaviors. When compared to genetically typical mice, the mice with the Scn2a genetic modification performed similarly in experiments for rudimentary learning and memory. In tests designed to evoke anxiety, typical mice appeared anxious, while the mice with the Scn2a mutation did not respond to the anxiety-inducing conditions. Similarly, some autistic individuals do not show fear responses in situations that others likely would find fearful. Mice with the Scn2a genetic mutation showed differences in their communication patterns and engaged in more repetitive behaviors than animals who did not have the mutation.

“It appears that SCN2A genetic mutations in mice primarily affect communication, and this occurs more often in males than females,” said Wetsel. “Every detail we analyze gets us closer to unraveling the secrets of how this gene governs complex brain mechanisms that lead to behaviors characteristic of autism.”