LTP involves the reorganization of AMPA receptors (AMPARs) in the postsynaptic membrane. Most current work on neural plasticity in mammals involves systems more tractable than intact brain, but it remains unclear how suitable these are as models for brain synapses. Therefore, Specific Aim 1 asks whether synapses in brain resemble synapses in slice-culture or cultured neurons. Excitatory synapses in hippocampus express AMPARs comprising GluR1, GluR2, and GluR3 subunits;GluR2 and GluR3 are trafficked and anchored at the synapse by the same mechanisms, distinct from the mechanisms that handle GluR1.
Specific Aim 2 uses immunogold electron microscopy to gain new insight into the organization of AMPA receptors at the synapse, to determine the organization of AMPAR subunits in a synapse, how their organization changes after LTP and LTD, and where new AMPARs are inserted in the synapse. Spine volume is correlated with the number of AMPA receptors in the synaptic membrane, implying that AMPAR expression must be coupled to spine size. While the causal relationship is not clear, this implies a linkage between the signaling pathways that mediate synaptic plasticity, and those that mediate changes in the actin cytoskeleton.
Specific Aim 3 examines how LIM kinase and Slingshot, two major proteins involved in the control of actin remodeling, are organized in a spine, whether their organization differs between large spines and small spines, and how their organization and level of activation may change after LTP/LTD. These studies will help to elucidate basic mechanisms underlying learning and memory. Their successful completion may help to gain new insight into the biological basis for memory disorders and mental retardation.
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