TARP γ-8 controls hippocampal AMPA receptor number, distribution and synaptic plasticity

Abstract

Synaptic plasticity involves activity-dependent trafficking of AMPA-type glutamate receptors. Numerous cytoplasmic scaffolding proteins are postulated to control AMPA receptor trafficking, but the detailed mechanisms remain unclear. Here, we show that the transmembrane AMPA receptor regulatory protein (TARP) γ-8, which is preferentially expressed in the mouse hippocampus, is important for AMPA receptor protein levels and extrasynaptic surface expression. By controlling the number of AMPA receptors, γ-8 is also important in long-term potentiation, but not long-term depression. This study establishes γ-8 as a critical protein for basal AMPA receptor expression and localization at extrasynaptic sites in the hippocampus and raises the possibility that TARP-dependent control of AMPA receptors during synapse development and plasticity may be widespread.

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Figure 1: γ-8 expression increases extrasynaptic but not synaptic AMPARs.
Figure 2: Targeted disruption of γ-8 decreases level of AMPAR proteins.
Figure 3: γ-8 mediates subcellular targeting of hippocampal AMPARs.
Figure 4: CA1 synaptic AMPAR-mediated responses are impaired in γ-8−/− mice.
Figure 5: CA3 synaptic AMPAR, but not KAR, responses are impaired in γ-8−/− mice.
Figure 6: Extrasynaptic AMPAR-mediated responses are severely reduced in hippocampus of γ-8−/− mice.
Figure 7: Impairment of LTP, but not LTD, in hippocampal CA1 synapses of γ-8−/− mice.

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Acknowledgements

We thank Y.-X. Wang for help in the immunogold studies, P. Seeburg for the GluRA−/− (GluR1−/−) mice and A. Tzingounis for discussion and reading the paper. This research was supported by grants (to D.S.B. and R.A.N) from the National Institutes of Health (NIH), the Howard Hughes Medical Institute Research Resources Program (to D.S.B.) and the Human Frontier Research Program (to D.S.B.). R.S.P. is supported by the Intramural Research Program of the NIH/NIDCD (National Institute on Deafness and Other Communication Disorders). R.A.N. is a member of the Keck Center for Integrative Neuroscience and the Silvo Conte Center for Neuroscience Research. D.S.B. is an established investigator for the American Heart Association. N.R. is supported by a fellowship from the International Human Frontier Science Program Organization. K.B. and S.T. are supported by postdoctoral fellowships from NIH.

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Correspondence to Roger A Nicoll.

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Supplementary information

Supplementary Fig. 1

Diagram depicting amount of GluR1 in the synaptic, extrasynaptic and cytoplasmic regions of hippocampal spines from γ-8−/− and γ-8+/+ mice. (PDF 832 kb)

Supplementary Methods (PDF 61 kb)

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Rouach, N., Byrd, K., Petralia, R. et al. TARP γ-8 controls hippocampal AMPA receptor number, distribution and synaptic plasticity. Nat Neurosci 8, 1525–1533 (2005). https://doi.org/10.1038/nn1551

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