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The Journal of Neuroscience, April 8, 2009, 29(14):4332-4345; doi:10.1523/JNEUROSCI.4431-08.2009

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Cellular/Molecular
Synaptic SAP97 Isoforms Regulate AMPA Receptor Dynamics and Access to Presynaptic Glutamate

Clarissa L. Waites,^1 * Christian G. Specht,^1 * Kai Härtel,² Sergio Leal-Ortiz,¹ David Genoux,² Dong Li,² Renaldo C. Drisdel,³ Okun Jeyifous,¹ Juliette E. Cheyne,² William N. Green,³ Johanna M. Montgomery,² and Craig C. Garner¹

¹Department of Psychiatry and Behavioral Sciences, Nancy Pritzker Laboratory, Stanford University, Palo Alto, California 94304-5485, ²Department of Physiology, University of Auckland, Auckland, New Zealand, and ³Department of Neurobiology, University of Chicago, Chicago, Illinois 60637

Correspondence should be addressed to Dr. Craig C. Garner, Department of Psychiatry and Behavioral Sciences, Nancy Pritzker Laboratory, Stanford University, 1201 Welch Road, Palo Alto, CA 94304-5485. Email: cgarner{at}stanford.edu

The synaptic insertion of GluR1-containing AMPA-type glutamate receptors (AMPARs) is critical for synaptic plasticity. However, mechanisms responsible for GluR1 insertion and retention at the synapse are unclear. The synapse-associated protein SAP97 directly binds GluR1 and participates in its forward trafficking from the Golgi network to the plasma membrane. Whether SAP97 also plays a role in scaffolding GluR1 at the postsynaptic membrane is controversial, attributable to its expression as a collection of alternatively spliced isoforms with ill-defined spatial and temporal distributions. In the present study, we have used live imaging and electrophysiology to demonstrate that two postsynaptic, N-terminal isoforms of SAP97 directly modulate the levels, dynamics, and function of synaptic GluR1-containing AMPARs. Specifically, the unique N-terminal domains confer distinct subsynaptic localizations onto SAP97, targeting the palmitoylated -isoform to the postsynaptic density (PSD) and the L27 domain-containing β-isoform primarily to non-PSD, perisynaptic regions. Consequently, - and βSAP97 differentially influence the subsynaptic localization and dynamics of AMPARs by creating binding sites for GluR1-containing receptors within their respective subdomains. These results indicate that N-terminal splicing of SAP97 can control synaptic strength by regulating the distribution of AMPARs and, hence, their responsiveness to presynaptically released glutamate.

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Received Sept. 16, 2008; revised Feb. 20, 2009; accepted Feb. 22, 2009.

Correspondence should be addressed to Dr. Craig C. Garner, Department of Psychiatry and Behavioral Sciences, Nancy Pritzker Laboratory, Stanford University, 1201 Welch Road, Palo Alto, CA 94304-5485. Email: cgarner{at}stanford.edu

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