Recent breakthroughs in antisense oligonucleotide (ASO) therapy have demonstrated that the damaging effects of some disease-causing mutations can be corrected in vivo. However, ASD susceptibility genes that are implicated by de novo mutations consist predominantly of dominant ‘haploinsufficiencies,’ for which ASO therapeutics have not yet been developed. Jonathan Sebat aims to demonstrate an approach to antisense therapy that is effective for boosting the expression level of specific ASD genes.

Neuronal activity triggers the expression of new genes that play a critical role in aspects of neural development and cognitive function. Building on evidence suggesting links between a class of ASD susceptibility loci (i.e., subunits of the BAF chromatin remodeling complex) and this form of gene regulation, Michael Greenberg and colleagues seek to determine whether disruption in neuronal activity-responsive chromatin remodeling underlies the effects of these ASD mutations.

Michael Hart plans to identify novel roles for known ASD risk genes in regulating GABAergic structural plasticity in the nematode C. elegans. He also plans to use unbiased forward genetic screens to identify novel genes that regulate structural plasticity. Findings from these studies may lead to a better understanding of neuronal and circuit plasticity changes associated with ASD pathogenesis.

Genetic variation in the SCN2A gene is a risk factor for ASD, but the functional consequences of the many different variants that have been identified to date remain unknown. In the current project, Alfred George plans to experimentally determine how genetic variants in SCN2A disrupt the function of the protein made from this gene. Results from the study will enable better categorization of variant pathogenicity and advance our knowledge about the molecular mechanisms through which SCN2A dysfunction can lead to ASD.