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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31MH070205-01
Application #
6738618
Study Section
Special Emphasis Panel (ZRG1-F03A (20))
Program Officer
Desmond, Nancy L
Project Start
2003-09-30
Project End
2006-09-29
Budget Start
2003-09-30
Budget End
2004-09-29
Support Year
1
Fiscal Year
2003
Total Cost
$33,917
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Correia, Susana S; Bassani, Silvia; Brown, Tyler C et al. (2008) Motor protein-dependent transport of AMPA receptors into spines during long-term potentiation. Nat Neurosci 11:457-66
Brown, Tyler C; Correia, Susana S; Petrok, Cortney N et al. (2007) Functional compartmentalization of endosomal trafficking for the synaptic delivery of AMPA receptors during long-term potentiation. J Neurosci 27:13311-5
Gerges, Nashaat Z; Brown, Tyler C; Correia, Susana S et al. (2005) Analysis of Rab protein function in neurotransmitter receptor trafficking at hippocampal synapses. Methods Enzymol 403:153-66
Brown, Tyler C; Tran, Irwin C; Backos, Donald S et al. (2005) NMDA receptor-dependent activation of the small GTPase Rab5 drives the removal of synaptic AMPA receptors during hippocampal LTD. Neuron 45:81-94