Application) This project contributes to the Center's overall objective by studying the molecular and cellular mechanisms of synaptic plasticity at the level of the single synapse. If changes in the strength of synaptic coupling between brain neurons is the basis of memory storage, as most neural models of learning assume, then the glutamatergic synapse, which is responsible for the vast majority of excitatory synaptic transmission in the brain, must play a key role. The project will use a combination of biophysical, molecular, and cellular techniques to study the mechanisms of synaptic plasticity at the level of individual synapses. The collaboration with Drs. Tonegawa and Heinemann extends these novel approaches to mutant mice, in which molecules vital for synaptic plasticity are deleted. The first set of experiments addresses the signaling pathways involved in the regulation of properties of the AMPA receptor, the glutamate receptor subtype responsible for generating most of the excitatory postsynaptic current. This will be achieved by studying properties of AMPA receptors in single synapses under pharmacological blockade and with genetic removal of several molecules such as NMDA receptor, CaM-KII, and calcineurin, which may participate in the regulation of postsynaptic AMPA receptors. Formation and elimination of synapses are proposed to be fundamental processes for long term plasticity of synaptic coupling between neurons. Although the role of neural activity in activity-dependent synaptic remodeling has been established, the issues of how patterns of neural activity affect the dynamic process of synapse remodeling and what signal pathway a neuron uses to translate neural activity into synaptic remodeling are still largely unknown. The second set of experiments uses an in vitro approach to study this form of synaptic plasticity and its regulation. We plan to address these questions by analyzing the role of neural activity in the early phase of synaptogenesis and by studying signal pathways that mediate activity-dependent synaptic remodeling using a combination of pharmacological and genetic approaches. We will interact closely with Dr. Bear, an expert on developmental plasticity in the visual cortex, on this project.
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