SYNGAP1 encodes a neuronal Ras GTPase activating protein and is a significant risk gene associated with autism spectrum disorders (ASDs) and intellectual disability (ID). As many of the genetic mutations in individuals with SYNGAP1-related ID (SRID) lead to decreased SYNGAP1 expression, SRID is an ideal candidate for genetic and antisense oligonucleotide–based therapies that increase SYNGAP1 expression. Leveraging recently discovered regulatory mechanisms of SYNGAP1 expression, Richard Huganir’s team plans to design precision antisense oligonucleotides that increase SYNGAP1 expression and to validate them using human pluripotent stem cell models of SRID. These studies will help to advance the therapeutic potential of antisense oligonucleotide–based treatments for SRID as well as other monogenic forms of ID and ASD.

Neurexin-neuroligin binding is essential for appropriate synaptic development and function, and mutations in neurexins and neuroligins have been linked to autism spectrum disorder (ASD). In the current project, Peng Zhang aims to assess how enhancements to and blockade of a specific heparan sulfate moiety alters neurexin function and whether such modulations can reverse synaptic deficits in a neurexin mouse model of ASD.

Ranmal Aloka Samarasinghe is studying brain organoids derived from individuals with mutations in SCN8A. Preliminary findings suggest that these organoids display excitatory-inhibitory imbalance and a loss of gamma oscillations. The current study aims to uncover the pathophysiological changes that underlie this observation and to test novel therapeutics that can rescue key cellular and physiological phenotypes in this model.