The long-term goal of this study is to understand mechanisms by which developing neocortical inhibitory circuits are able to adapt to sensory inputs from the peripheral sense organs, and to maintain their balance with the cortical excitatory circuits in the sensory cortex. During brain development, neurons in the cerebral cortex establish connections that are then fine tuned by experience-dependent mechanisms. Although much is now known regarding processes of glutamatergic maturation and activity-dependent modification of glutamatergic synapses for network formation, postnatal development of neocortical GABAergic synapses and their role in activity-dependent modification remains unclear. Mechanisms that match excitation and inhibition are central to attaining balanced function at the level of single neurons and brain circuits. Disturbances in the balance between excitation and inhibition in the neocortex provoke abnormal activities, such as epileptic seizures. The central hypothesis examined by this proposal is that the spike-timing dependent long-term plasticity of glutamatergic synapses in inhibitory interneurons plays an important role in experience-dependent refinement of interneuronal networks. The proposed research will utilize a combination of electrophysiological recording, pharmacological manipulations and quantitative immunohistological analysis to examine mechanisms underlying experience-dependent maturation of intracortical inhibitory networks. The synaptic strength underlying cortical plasticity will be measured from green-fluorescent protein labeled interneurons from brain slices prepared from transgenic mice, in which whisker experience was altered in the postnatal periods. This approach allows linkages to be made between amounts of intracortical synaptic plasticity recorded in vitro and previous sensory experiences in vivo. Successful completion of this study will provide a comprehensive view of the roles of sensory experiences in shaping inhibitory synaptic connectivity at early stages of life and mechanisms underlying excitation and inhibition balancing. This information could have implications for developing novel treatment strategies for developmental neurological and psychiatric disorders that result from aberrant connectivity among neocortical principal neurons and interneurons. ? ? ?
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