Abstract Autism spectrum disorders are clinically and genetically heterogeneous. Identification of convergent molecular pathways and neural circuits underlying autism endophenotypes are crucial to discovery of novel drug targets for development of effective therapies. Glutamate mediates the majority of excitatory neurotransmission in the CNS. Glutamate receptor interacting proteins 1/2 (GRIP1/2) are neuron-enriched scaffolding proteins with 7 PDZ domains. PDZ domains 4-6 of GRIP1/2 bind the c-terminal domain of AMPA receptor 2/3 (GluA2/3). Loss of Grip1/2 expression in mice results in delayed recycling of GluA2 in neurons and increased sociability and social interactions. Studies of AMPA-signaling proteins identified an enhanced GluA2-S880 phosphorylation in prefrontal cortex in the mutant mice. In a screen of glutamate signaling genes in patients with autism, we found gain-of-function mutations in GRIP1-PDZ4-6 that contribute to reduced social interactions in autism patients. To study mechanisms of GluA2 trafficking in modulating social behaviors, we generated knock-in mice carrying a human autism-associated mutation I586L. Grip1-I586L mice show increased binding with GluA2 in brain lysates and exhibit a reduced sociability in the modified three-chamber sociability tests. We hypothesize that Grip1-I586L alter GluA2 recycling and surface expression resulting in increased AMPA synaptic strength and enhanced local connectivity in prefrontal cortex. We will study molecular mechanisms responsible for GluA2 trafficking defects in Grip1-KO and Grip1-I586L mice. We will investigate neural mechanisms of disturbance of AMPA signaling in prefrontal cortex causing social behavioral deficits in autism using electrophysiology and optogenetic methods. The results shall provide valuable insights into neural mechanisms of AMPA signaling defects in social behavioral deficits in autism.