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TARP γ-7 selectively enhances synaptic expression of calcium-permeable AMPARs

Nature Neuroscience volume 16, pages 12661274 (2013) | Download Citation

Abstract

Regulation of calcium-permeable AMPA receptors (CP-AMPARs) is crucial in normal synaptic function and neurological disease states. Although transmembrane AMPAR regulatory proteins (TARPs) such as stargazin (γ-2) modulate the properties of calcium-impermeable AMPARs (CI-AMPARs) and promote their synaptic targeting, the TARP-specific rules governing CP-AMPAR synaptic trafficking remain unclear. We used RNA interference to manipulate AMPAR-subunit and TARP expression in γ-2–lacking stargazer cerebellar granule cells—the classic model of TARP deficiency. We found that TARP γ-7 selectively enhanced the synaptic expression of CP-AMPARs and suppressed CI-AMPARs, identifying a pivotal role of γ-7 in regulating the prevalence of CP-AMPARs. In the absence of associated TARPs, both CP-AMPARs and CI-AMPARs were able to localize to synapses and mediate transmission, although their properties were altered. Our results also establish that TARPed synaptic receptors in granule cells require both γ-2 and γ-7 and reveal an unexpected basis for the loss of AMPAR-mediated transmission in stargazer mice.

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Acknowledgements

This work was supported by Programme Grants from the Wellcome Trust and the Medical Research Council (S.G.C.-C. and M.F.). We thank M. Watanabe for antibodies against γ-2 and γ-7, R. Nicoll for TARP γ-2 cDNA, C. Bats for invaluable discussions and M. Zonouzi and M. Watanabe for advice on coimmunoprecipitation.

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  1. Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.

    • Dorota Studniarczyk
    • , Ian Coombs
    • , Stuart G Cull-Candy
    •  & Mark Farrant

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Contributions

S.G.C.-C. and M.F. conceived and supervised the project. D.S. performed electrophysiological and biochemical experiments. M.F. and D.S. analyzed the data. I.C. generated reagents for RNA interference and performed biochemical experiments. D.S., S.G.C.-C. and M.F. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Stuart G Cull-Candy or Mark Farrant.

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https://doi.org/10.1038/nn.3473

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