A promising and widely studied example of vertebrate synaptic plasticity is long-term potentiation (LTP), the persistent synaptic enhancement seen following a brief period of coincident pre- and postsynaptic activity. It has been suggested that the cellular and molecular mechanisms responsible for LTP will elucidate physiological and pathological phenomena including learning, memory, developmental synapse specificity, pain, neuronal death, epilepsy and dementia. A number of recent studies indicate that regulated synaptic delivery of AMPA receptors (-Rs) is a critical aspect of LTP. Here we will examine molecular mechanisms controlling the regulated synaptic delivery of AMPA-Rs The central hypothesis to be tested is that protein kinases drive AMPA-Rs to synapses by relieving their extrasynaptic retention. We will examine the role of two protein kinases, PKA and CaMKII, in controlling retention interactions that keep AMPA-Rs extrasynaptically. This will be examined early in development, when GluR4 controls synaptic delivery, and later in life, when synaptic delivery is controlled by GluR1. Several complementing methodologies will be used, including molecular biology, electrophysiology, two-photon imaging of GFP-tagged receptors, and immunohistochemistry with light and electron microscopy. These studies will use organotypic rat hippocampal slices.
The specific aims are to determine the mechanism by which: SA1: PKA controls synaptic delivery of GluR4-eontaining-AMPA-R early in postnatal development. SA2: PKA controls synaptic delivery of GluR1-containing-AMPA-R driven by CaMKII later in life. SA3: PKA controls generation of LTP later in life. SA4: extrasynaptic retention of AMPA-Rs is regulated by protein-protein interactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS032827-09
Application #
6579151
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Talley, Edmund M
Project Start
1995-04-01
Project End
2008-02-29
Budget Start
2003-04-01
Budget End
2004-02-29
Support Year
9
Fiscal Year
2003
Total Cost
$535,157
Indirect Cost
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
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