Recent genome-wide association studies of Intellectual disability (ID), Autism spectrum disorder (ASD) and Schizophrenia (SCZ) have improved our understanding of the molecular and cellular basis of human cognitive diseases. Functional categorization of these genes has revealed a significant enrichment of mutations affecting glutamatergic synapse structure and function. One protein that has been shown to regulate glutamatergic synapses is SynGAP, a RasGAP that is a critical negative regulator of spine morphogenesis and synaptic plasticity via Ras-ERK and protein synthesis-dependent signaling pathways. De Novo deleterious SYNGAP mutations are estimated to account for approximately 1% of ID cases and are highly comorbid with ASD. SYNGAP variants have also been found to be a significant risk factor in other neuropsychiatric disorders including SCZ and bipolar disorder (BP). We recently identified SynGAP as one of the most potent regulators of synaptic size and/or number using a high-throughput screen of 200 SCZ-associated risk genes. In addition, we found that ID/ASD-associated SynGAP mutations also affect synaptic structure and function. These data support the notion that human SynGAP mutations might alter synaptic transmission and plasticity. To determine how disease-associated SynGAP mutations impact synaptic pathophysiology and behavior, we will first characterize the effect of SYNGAP disease risk variants on synapse structure and function using a combination of approaches including real time imaging, biochemical and electrophysiological techniques. Next, we will use CRISPR/Cas9 genome editing to generate mouse models carrying SynGAP mutations that precisely mimic human disease risk variants of SynGAP. With these mice we will determine whether they have differential plasticity, circuit and behavioral phenotypes. Finally, we will perform mechanism based drug screens to target disrupted SynGAP-regulated signal transduction pathways to discover small molecule(s) that can ameliorate synaptic and behavioral deficits. This proposed project would be the first systematic investigation of disease-associated SynGAP mutations on synaptic pathophysiology and animal behavior. These studies will allow us to gain insight into mechanisms underlying SynGAP-associated diseases and pave the way for novel therapeutic strategies.
SynGAP, a critical regulator of glutamatergic synaptic structure and function through its Ras-ERK and protein synthesis signaling, is one of the most prominent genes identified in psychiatric diseases and neurodevelopmental disorders. We will characterize SYNGAP disease risk variants and generate knockin mice that carry disease associated SYNGAP mutations to study their functional impact and develop potential therapeutics to treat these disorders.
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