Experience-Dependent Reorganization of Excitatory Synapse Connectivity

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Overwhelming genetic evidence in neuropsychiatric disorders points towards the excitatory synapse and plasticity components, essential for experience-dependent optimization of the neural circuit. This leads to the hypothesis that dysregulation in experience-dependent developmental plasticity caused by the molecular and cellular deficit leads to behavioral abnormalities. It is therefore essential to understand how experience sculpts the functional connection of excitatory synapses during development; and how under the pathological condition, this impaired mechanism derails the normal developmental trajectory. Using the mouse primary visual cortex (V1) as the model system, we have shown that during the functional maturation of excitatory synapses, AMPA receptor-mediated synaptic transmission remains at equilibrium during the critical period. The maintenance of this equilibrium requires neurogranin (Ng), a postsynaptic calmodulin (CaM)-binding protein important for synaptic plasticity, which is associated with schizophrenia and mental retardation. Two antagonizing mechanisms, experience-dependent AMPAR-silent synapse conversion and experience-dependent synapse elimination, hinge upon Ng for constructive synaptic refinement during the critical period. Our preliminary studies show that decreasing Ng levels led to delayed developmental switch of the NMDA receptor subunits, and shift in neuronal phosphorylation profiles. We hypothesize that Ng regulates experience-dependent organization of excitatory synaptic connectivity via controlling Ca/CaM- dependent phosphatase activities, which determine synaptic NMDAR composition and activity during development (critical components associated with schizophrenia). Using a combination of virus-mediated gene manipulation, electrophysiology, morphological analysis and behavioral interrogation, we will elucidate the molecular pathways governing experience-dependent refinement of excitatory synaptic connectivity during development, essential for sensory perception. Our study will help understand the molecular mechanisms important for calcium homeostasis in health and diseases, and may provide therapeutic substrate for pharmacological interventions for schizophrenia patients.