Noncanonical RNA Splicing and Liquid-Liquid Phase Separation of SynGAP1: Novel Mechanisms Underlying Synaptic Plasticity and Cognition

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Project Summary Recent genetic studies of intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy (EPI) have revealed a significant association of these disorders with genes encoding proteins involved in glutamatergic synapse structure and function. One key protein known to regulate glutamatergic synapses is SynGAP1, a RasGAP critical for synaptic plasticity, learning, memory, and cognition. Deleterious mutations in SYNGAP1 in humans result in intellectual disability, autistic-like behaviors, and epilepsy. Knock-in model mice with mutations found in humans and heterozygous Syngap1 knock-out mice exhibit deficits in synaptic plasticity, learning, and memory, as well as seizures. We have recently discovered that the catalytic activity of SynGAP1's GAP domain is not required for synaptic plasticity and normal behavior in mice. Instead, SynGAP1 plays a unique structural role at the synapse, forming complexes with synaptic scaffolding proteins and dynamically regulating synapse structure and function. In addition, we have recently discovered that the mRNA splicing of the α1 splice variant of SynGAP1, the most significant isoform of SynGAP1 for synaptic complex formation and synaptic plasticity, occurs through a unique non-canonical splicing mechanism. Here, using a combination of molecular biological, biochemical, cell biological, and in vivo studies, we propose to investigate the structure and function of SynGAP1 critical for synapse complex formation, synaptic plasticity, and cognition. Moreover, using molecular biological, cell biological, and in vivo studies, we will characterize the molecular mechanisms underlying the unique noncanonical splicing of SYNGAP1 required for synapse complex formation, synaptic plasticity, and cognition. These studies will not only reveal novel mechanisms underlying the regulation of SynGAP1 function but will also uncover new pathways and candidates for therapies to cure SYNGAP1-related Intellectual Disability (SRID) and other SynGAP1-related disorders.