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J. Biol. Chem., Vol. 283, Issue 48, 33138-33146, November 28, 2008

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Long Term Synaptic Depression That Is Associated with GluR1 Dephosphorylation but Not -Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Internalization^*

Kurtis D. Davies, Susan M. Goebel-Goody, Steven J. Coultrap, and Michael D. Browning¹

From the Department of Pharmacology and Program in Neuroscience, University of Colorado Health Sciences Center, Aurora, Colorado 80045

Long lasting changes in the strength of synaptic transmission in the hippocampus are thought to underlie certain forms of learning and memory. Accordingly, the molecular mechanisms that account for these changes are heavily studied. Postsynaptically, changes in synaptic strength can occur by altering the amount of neurotransmitter receptors at the synapse or by altering the functional properties of synaptic receptors. In this study, we examined the biochemical changes produced following chemically induced long term depression in acute hippocampal CA1 minislices. Using three independent methods, we found that this treatment did not lead to an internalization of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Furthermore, when the plasma membrane was separated into synaptic membrane-enriched and extrasynaptic membrane-enriched fractions, we actually observed a significant increase in the concentration of AMPA receptors at the synapse. However, phosphorylation of Ser-845 on the AMPA receptor subunit GluR1 was significantly decreased throughout the neuron, including in the synaptic membrane-enriched fraction. In addition, phosphorylation of Ser-831 on GluR1 was decreased specifically in the synaptic membrane-enriched fraction. Phosphorylation of these residues has been demonstrated to control AMPA receptor function. From these data, we conclude that the decrease in synaptic strength is likely the result of a change in the functional properties of AMPA receptors at the synapse and not a decrease in the amount of synaptic receptors.

Received for publication, May 6, 2008 , and in revised form, September 25, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Research Grants AA014691 and AA09675. M. D. B. has a financial interest in PhosphoSolutions, a company that provided several of the antibodies used in this study. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: University of Colorado Health Sciences Center, Dept. of Pharmacology, Mail Stop 8303, P. O. Box 6511, Aurora, CO 80045-0511. Tel.: 303-724-3638. Fax: 303-724-3640. E-mail: michael.browning{at}uchsc.edu.

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