This is a proposal for renewal of RO1 MH053608 that examines the immediate early gene Arc, its role in activity- dependent synaptic plasticity, and its contribution to diseases that impact mental health. Our plans focus on a novel function of Arc that mediates AKT signaling down-stream of the NMDA receptor. This mechanism is distinct from canonical functions of Arc that mediate synaptic scaling and long-term depression. Preliminary studies suggest that NMDAR-Arc-AKT signaling stabilizes NMDAR expression at the membrane and may contribute to metaplastic synaptic potentiation. NMDAR, Arc and AKT are each suspected hubs for schizophrenia, and proposed studies seek to understand both the natural function of NMDAR-Arc-AKT signaling and how disruption of this pathway may contribute to schizophrenia. Aim 1 examines the protein composition, assembly, NMDA receptor pharmacology, synapse specificity of the signaling pathway, and its role in synaptic plasticity. Aim 2 examines NMDAR-Arc-AKT signaling in vivo and examines its hypothesized role to potentiate D1 receptor signaling, its role in the establishment of behaviorally linked ensembles of excitatory neurons, and to discover adaptions to disruption of the pathway that cause hyperdopaminergic signaling. Aim 3 tests the prediction that NMDAR-Arc-AKT signaling is important for adaptation to stress that can induce schizophrenia-like endophenotypes in vulnerable animals, and examines a hypothetical mechanism that is based on human and mouse studies suggesting failure of interneuron mechanisms. Aim 4 will examine the NMDAR-Arc-AKT complex and signaling in human brain and iPS neurons in collaboration with the Lieber Institute for Brain Development. Studies will create and compare protein and RNAseq biomarkers from mouse models representing failure of NMDAR-Arc-AKT complex formation and signaling, and compare these with best available databases from human subjects with well characterized genetic load for schizophrenia. Our hope is to confirm a role for the NMDAR-Arc-AKT pathway as a basis for risk in polygenetic human disease.