Project Summary A goal of basic mental health research is to understand the molecular, cellular and circuit level substrates that contribute to neuropsychiatric disorders. The goal of this project is to better understand the principles underlying circuit dysfunction associated with cognitive and social impairments common to these disorders. A promising approach to better understand these substrates is to perform in-depth studies in animal models with high construct and face validities. De novo pathogenic SYNGAP1 mutations leading to haploinsufficiency cause one the most common genetically defined and non-inherited forms of intellectual disability (ID) with autism spectrum disorder (ASD;? termed MRD5;? OMIN# 612621). Studies supported by the first budget period identified Syngap1 heterozygous KO mice as an outstanding genetic model of ASD with ID. Using this model, we discovered a developmental sensitive period of Syngap1 function that promotes the proper function of cortical networks. The neurobiological studies we published in the last period were significant because they identified the developmental timing of dendrite and spine maturation selectivity within forebrain excitatory neurons as a critical substrate that shapes brain function relevant to cognitive and social development. For this competitive renewal, we will build on our discoveries in the first budget period by studying the key substrates of circuit dysfunction in the Syngap1 model by probing how this gene regulates cortical sensory processing relevant to cognition and learning. This approach is significant because sensory impairments are extremely common in ASD/ID and these impairments influence behavioral adaptations, including learning. Syngap1 patients express sensory abnormalities related to touch and pain. However, the circuit abnormalities that underlie sensory dysfunction are unclear. Thus, our approach is innovative because studies will be performed in the mouse somatosensory cortex, which will enable powerful in vivo experiments that are capable of directly linking cellular- and circuit-level functional impairments to sensory-based learning and behavioral abnormalities. The first Aim will investigate the cellular mechanisms underlying impaired somatosensory cortex network function caused by pathogenic Syngap1 mutations, with an emphasis on how network-level E/I imbalances emerge within cortical circuits that directly encode sensory representations. Research proposed in the second Aim will determine the cellular mechanisms that contribute to sensory-driven learning impairments in Syngap1 mice. The impact of these studies is that they are expected to advance our understanding how cortical circuit dysfunction leads to behavioral impairments associated with ASD/ID.