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J. Biol. Chem., Vol. 280, Issue 17, 16962-16968, April 29, 2005

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Role for A Kinase-anchoring Proteins (AKAPS) in Glutamate Receptor Trafficking and Long Term Synaptic Depression^*

Eric M. Snyder, Marcie Colledge¶||, Robert A. Crozier, Wendy S. Chen, John D. Scott¶, and Mark F. Bear**

From the Howard Hughes Medical Institute, The Picower Center for Learning and Memory and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 and ^¶Howard Hughes Medical Institute, Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239

Expression of N-methyl D-aspartate (NMDA) receptor-dependent homosynaptic long term depression at synapses in the hippocampus and neocortex requires the persistent dephosphorylation of postsynaptic protein kinase A substrates. An attractive mechanism for expression of long term depression is the loss of surface AMPA (-amino-3-hydroxy-5-methylisoxazale-4-propionate) receptors at synapses. Here we show that a threshold level of NMDA receptor activation must be exceeded to trigger a stable loss of AMPA receptors from the surface of cultured hippocampal neurons. NMDA also causes displacement of protein kinase A from the synapse, and inhibiting protein kinase A (PKA) activity mimics the NMDA-induced loss of surface AMPA receptors. PKA is targeted to the synapse by an interaction with the A kinase-anchoring protein, AKAP79/150. Disruption of the PKA-AKAP interaction is sufficient to cause a long-lasting reduction in synaptic AMPA receptors in cultured neurons. In addition, we demonstrate in hippocampal slices that displacement of PKA from AKADs occludes synaptically induced long term depression. These data indicate that synaptic anchoring of PKA through association with AKAPs plays an important role in the regulation of AMPA receptor surface expression and synaptic plasticity.

Received for publication, August 23, 2004 , and in revised form, February 11, 2005.

^* This work was supported in part by National Institutes of Health Grants GM48231 (to J. D. S.) and NS39321 (to M. F. B.). 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.

Both authors contributed equally to work.

^|| Present address: Dept. of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390.

^** To whom correspondence should be addressed: MIT, E19–551, 77 Massachusetts Ave., Cambridge, MA 02139. Tel.: 617-324-7002; Fax: 617-324-7007; E-mail: mbear{at}mit.edu.

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