Haploinsufficiency of in Striatal Indirect Pathway Neurons Alters Motor and Goal-Directed Behaviors in Mice.

is a high-confidence autism spectrum disorder (ASD) risk gene, and mutations in lead to a neurodevelopmental disorder (NDD) that presents with epilepsy, ASD, motor developmental delay, and intellectual disability. codes for Ras/Rap GTP-ase activating protein SynGAP (SynGAP). SynGAP is located in the postsynaptic density of glutamatergic synapses and regulates glutamate receptor trafficking in an activity-dependent manner. In addition to forebrain glutamatergic neurons, is highly expressed in the striatum, although the functions of SynGAP in the striatum have not been extensively studied. Here we show that is expressed in both direct and indirect pathway striatal projection neurons (dSPNs and iSPNs) in mice of both sexes. In a mouse model of haploinsufficiency, dendritic spine density, morphology, and intrinsic excitability are altered primarily in iSPNs, but not dSPNs. At the behavioral level, SynGAP reduction alters striatal-dependent motor learning and goal-directed behavior. Several behavioral phenotypes are reproduced by iSPN-specific reduction and, in turn, prevented by iSPN-specific rescue. These results establish the importance of SynGAP to striatal neuron function and pinpoint the indirect pathway as a key circuit in the neurobiology of -related NDD.