Investigating Syngap1 as a regulator of striatal synaptic function

项目总结

PROJECT SUMMARY SYNGAP1-related intellectual disability is a neurodevelopmental disorder caused by mutations in the SYNGAP1 gene. SYNGAP1 encodes 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 cultured neurons. 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 well- 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, which receive excitatory inputs from the cortex. SynGAP is therefore positioned to play a key role in gating transmission and plasticity at striatal synapses. Despite this, SynGAP’s functions in striatal neurons have not yet been defined. Importantly, several of the major symptoms of SYNGAP1 disorder are likely to involve alterations in striatal activity including motor developmental delay, repetitive and restrictive behaviors, and other behavioral problems. In this project, 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, we will determine how loss of SynGAP impacts striatal synaptic development, transmission and plasticity. In addition, we will use imaging approaches to investigate how SynGAP deficiency affects spinogenesis, spine number and morphology. To determine whether deletion of Syngap1 from striatal neurons is sufficient to alter disease-relevant behaviors, we will investigate how haploinsufficiency of Syngap1 in cell type-specific knock-out mice affects motor function, habit learning, and behavioral flexibility. Finally, we will test whether restoration of Syngap1 expression selectively in striatal projection neurons can improve synaptic and behavioral abnormalities using genetic rescue strategies. Together, this work will 1) further our understanding of SynGAP’s functions at striatal synapses, 2) identify the striatal cell type(s) most relevant for the manifestations of SYNGAP1 disorder, and 3) define critical periods for the onset and rescue of disease-related phenotypes.