Abstract
Long-term potentiation (LTP) of synaptic transmission is thought to be an important cellular mechanism underlying memory formation. A widely accepted model posits that LTP requires the cytoplasmic carboxyl tail (C-tail) of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GluA1. To find the minimum necessary requirement of the GluA1 C-tail for LTP in mouse CA1 hippocampal pyramidal neurons, we used a single-cell molecular replacement strategy to replace all endogenous AMPA receptors with transfected subunits. In contrast to the prevailing model, we found no requirement of the GluA1 C-tail for LTP. In fact, replacement with the GluA2 subunit showed normal LTP, as did an artificially expressed kainate receptor not normally found at these synapses. The only conditions under which LTP was impaired were those with markedly decreased AMPA receptor surface expression, indicating a requirement for a reserve pool of receptors. These results demonstrate the synapse’s remarkable flexibility to potentiate with a variety of glutamate receptor subtypes, requiring a fundamental change in our thinking with regard to the core molecular events underlying synaptic plasticity.
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Acknowledgements
We thank A. Jackson, J. Levy, S. Fischbach, K. Lovero, N. Sheng, S. Shipman and M. Younger for critical discussions and reading of the manuscript; K. Bjorgen for technical help with organotypic slice cultures; and L. Subramanian from the Kriegstein laboratory for technical help with in utero electroporations. We thank P. Seeburg and R. Sprengel for the Gria1–3fl/fl mice. A.J.G. was supported by the National Science Foundation Graduate Research Fellowship. R.A.N. is supported by the National Institute of Health.
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M.C. carried out electroporations and maintained Gria1–3fl/fl mice. Y.S. collected GluK1 overexpression data. W.L. was involved in study design and cloned several constructs. A.J.G. designed the study, collected and analysed data, and wrote the paper. R.A.N. conceived the study, contributed to the design of experiments and wrote the paper. All authors discussed the results and commented on the manuscript.
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Granger, A., Shi, Y., Lu, W. et al. LTP requires a reserve pool of glutamate receptors independent of subunit type. Nature 493, 495–500 (2013). https://doi.org/10.1038/nature11775
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DOI: https://doi.org/10.1038/nature11775
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