The remodeling of connections between neurons, known as synaptic plasticity, is essential for learning and memory. Alterations in synaptic plasticity have been implicated in the pathology of several neurological disorders, including schizophrenia and Alzheimer's disease. One important mechanism for synaptic plasticity is the regulated trafficking of AMPA-type glutamate receptors (AMPA Rs) in and out of synapses. We propose to investigate whether Rab5a is involved in the regulated removal of synaptic AMPA Rs during plasticity. Preliminary evidence suggests that expression of a recombinant RabEa protein, a small GTPase that mediates intracellular membrane trafficking, results in the specific removal of AMPA Rs from excitatory synapses in the rat hippocampus. We will use the Sindbis virus expression system to express recombinant Rab5a constructs and/or specific subunits of the AMPA R (GluR1-3) in organotypic slice cultures of the rat hippocampus. Receptor trafficking will be monitored by electrophysiology, biochemistry, and immunogold electron microscopy. We propose that delineating the signaling pathways involved in Rab5a-mediated trafficking of AMPA Rs could lead to a better understanding of neurological disorders that alter synaptic plasticity and provide a greater insight into learning and memory processes. ? ?
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