Project Summary Optimal refinement of neural circuits during development is a highly controlled process that depends critically on experience. Ample genetic evidence in mental disorders points specifically to defects in molecular targets related to experience-dependent developmental plasticity of excitatory synapses, and dysregulation of this fundamental developmental process results in a variety of neuropsychiatric diseases. This project seeks to elucidate mechanisms by which experience sculpts the functional connection of excitatory synapses during development and how perturbations in this process can derail the normal developmental trajectory. We found that during the critical period of their functional maturation, excitatory synapses of the mouse primary visual cortex (V1) maintain a dynamic equilibrium in their AMPA receptor-mediated transmission. This equilibrium requires neurogranin (Ng), a postsynaptic calmodulin-binding protein important for synaptic plasticity, which is has been implicated in schizophrenia and mental retardation. Our preliminary studies show that in addition to controlling incorporation of AMPA receptors into AMPA receptor-lacking (silent) synapses and synaptic pruning, Ng levels also control the timing of the developmental switch in NMDA receptor subunits, and change the phosphorylation profiles of several post synaptic proteins including NMDA receptor and PSD-93/95. This project investigates the hypothesis that Ng levels influence the experience-dependent reorganization of excitatory synaptic connectivity by altering Ca/CaM-dependent signaling pathways, including PP2B and NMDA receptors, using a combination of virus- mediated gene manipulation, synaptic physiology, channel biophysics, morphological analysis, and behavioral interrogation. The results will elucidate the molecular pathways governing experience-dependent refinement of excitatory synaptic connectivity during development and will help to identify potential targets for pharmacologic interventions in patient with neurodevelopmental disorders.