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J. Biol. Chem., Vol. 279, Issue 42, 43870-43878, October 15, 2004

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Local Control of AMPA Receptor Trafficking at the Postsynaptic Terminal by a Small GTPase of the Rab Family^*

Nashaat Z. Gerges, Donald S. Backos, and José A. Esteban

From the Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0632

The delivery of neurotransmitter receptors into the synaptic membrane is essential for synaptic function and plasticity. However, the molecular mechanisms of these specialized trafficking events and their integration with the intracellular membrane transport machinery are virtually unknown. Here, we have investigated the role of the Rab family of membrane sorting proteins in the late stages of receptor trafficking into the postsynaptic membrane. We have identified Rab8, a vesicular transport protein associated with trans-Golgi network membranes, as a critical component of the cellular machinery that delivers AMPA-type glutamatergic receptors (AMPARs) into synapses. Using electron microscopic techniques, we have found that Rab8 is localized in close proximity to the synaptic membrane, including the postsynaptic density. Electrophysiological studies indicated that Rab8 is necessary for the synaptic delivery of AMPARs during plasticity (long-term potentiation) and during constitutive receptor cycling. In addition, Rab8 is required for AMPAR delivery into the spine surface, but not for receptor transport from the dendritic shaft into the spine compartment or for delivery into the dendritic surface. Therefore, Rab8 specifically drives the local delivery of AMPARs into synapses. These results demonstrate a new role for the cellular secretory machinery in the control of synaptic function and plasticity directly at the postsynaptic membrane.

Received for publication, May 5, 2004

^* This work was supported by grants from the National Institutes of Health (Grant MH070417), National Alliance for Research on Schizophrenia and Depression, and Alzheimer's Association (to J. A. E.). 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.

To whom correspondence should be addressed: Dept. of Pharmacology, University of Michigan Medical School, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0632. Tel.: 734-615-2686; Fax: 734-763-4450; E-mail: estebanj{at}umich.edu.

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