Journal
JOURNAL OF NEUROSCIENCE
Volume 29, Issue 14, Pages 4332-4345Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4431-08.2009
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Funding
- NIDA NIH HHS [R01 DA013602, DA 019695, DA 016758, DA 13602, R01 DA016758-05, R01 DA016758, P01 DA019695] Funding Source: Medline
- NIMH NIH HHS [R21 MH085954, R21 MH085954-02] Funding Source: Medline
- NINDS NIH HHS [R56 NS043782, NS 043782, R01 NS043782] Funding Source: Medline
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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 alpha-isoform to the postsynaptic density (PSD) and the L27 domain-containing beta-isoform primarily to non-PSD, peri-synaptic regions. Consequently, alpha- and beta SAP97 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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