SYNGAP1-related non-syndromic intellectual disability is a neurodevelopmental disorder caused by mutations in the SYNGAP1 gene. SYNGAP1 encodes the protein SynGAP, which is a highly abundant protein in the post-synaptic density of excitatory synapses. At synapses, SynGAP functions to repress downstream NMDAR signaling and AMPAR trafficking through its inhibition of small GTPases. Translocation of SynGAP out of the post-synaptic density is required to allow NMDAR-dependent long- term potentiation (LTP). In the absence of SynGAP, NMDAR-dependent plasticity is unrestrained leading to alterations in synapse strength, spine structure, and plasticity. While the functions of SynGAP have been nearly exclusively studied in the cortex and hippocampus, the striatum also exhibits high levels of SynGAP expression. Striatal projection neurons are GABA-ergic neurons covered in a dense array of dendritic spines that receive excitatory input from multiple cortical areas. SynGAP is therefore positioned to play a key role in gating synaptic transmission and plasticity at corticostriatal synapses. Despite this, SynGAP?s functions in striatal synaptic physiology have not yet been defined. Moreover, several of the major symptoms of SYNGAP1 disorder likely involve striatal pathophysiology including autism spectrum disorder, obsessive-compulsive behavior, motor developmental delay, hyperexcitability, and other behavioral problems. In this exploratory study, we will elucidate the consequences of SynGAP loss on striatal synaptic function and determine whether loss of SynGAP from striatal neurons is sufficient to induce behavioral alterations relevant for SYNGAP1 disorder. Specifically, in Aim 1 we will determine how loss of SynGAP impacts corticostriatal synaptic transmission and plasticity. In addition, we will use advanced imaging approaches to investigate how SynGAP deficiency affects dendritic spine number and morphology.
In Aim 2, we will determine whether deletion of Syngap1 from specific striatal cell types is sufficient to alter motor behaviors, habit learning, and cognitive flexibility. We will further test whether restoration of SynGAP expression only in striatal projection neurons is capable of preventing behavioral abnormalities using a genetic rescue strategy. Together, this work will provide an essential starting point for understanding SynGAP?s functions at striatal synapses and identify the striatal cell type(s) most relevant for the manifestations of SYNGAP1-related disorders.
This research will provide new information about how mutations in Syngap1, which cause SYNGAP1- related non-syndromic intellectual disability, affect communication between brain cells responsible for the selection and learning of appropriate actions. Our findings will advance our understanding of the cellular and circuit basis of SYNGAP1 disorders and can be leveraged to improve therapeutic possibilities for patients with this and related diseases.
