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The AMPA Receptor Subunit GluA1 is Required for CA1 Hippocampal Long-Term Potentiation but is not Essential for Synaptic Transmission

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Abstract

AMPA receptors mediate the majority of excitatory glutamatergic transmission in the mammalian brain and are heterotetramers composed of GluA1-4 subunits. Despite genetic studies, the roles of the subunits in synaptic transmission and plasticity remain controversial. To address this issue, we investigated the effects of cell-specific removal of GluA1 in hippocampal CA1 pyramidal neurons using virally-expressed GluA1 shRNA in organotypic slice culture. We show that this shRNA approach produces a rapid, efficient and selective loss of GluA1, and removed > 80% of surface GluA1 from synapses. This loss of GluA1 caused a modest reduction (up to 57%) in synaptic transmission and when applied in neurons from GluA3 knock-out mice, a similar small reduction in transmission occurred. Further, we found that loss of GluA1 caused a redistribution of GluA2 to synapses that may compensate functionally for the absence of GluA1. We found that LTP was absent in neurons lacking GluA1, induced either by pairing or by a theta-burst pairing protocol previously shown to induce LTP in GluA1 knock-out mice. Our findings demonstrate a critical role of GluA1 in CA1 LTP, but no absolute requirement for GluA1 in maintaining synaptic transmission. Further, our results indicate that GluA2 homomers can mediate synaptic transmission and can compensate for loss of GluA1.

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Abbreviations

LTP:

Long-term potentiation

AMPA:

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid

NMDA:

N-methyl-d-aspartate

CA1:

Cornu ammonis 1

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Acknowledgements

We are very grateful to Dr Katherine Roche for extensive help, advice and support for this work. We thank Dr Zhengping Jia for providing the GluA3 knock-out mice. Supported by the NINDS Intramural Program.

Author information

Author notes

  1. Akira Terashima

    Present address: Department of Aging Brain and Cognitive Disorders, Hyogo Brain and Heart Center, 520 Saisho-Kho, Himeji, Hyogo, 670-0981, Japan

  2. Young Ho Suh

    Present address: Neuroscience Research Institute, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea

  3. John T. R. Isaac

    Present address: Johnson & Johnson Innovation Centre, One Chapel Place, London, W1G 0BG, UK

Authors and Affiliations

  1. Developmental Synaptic Plasticity Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 35 Convent Drive, Bethesda, MD, 20892, USA

    Akira Terashima & John T. R. Isaac

  2. Receptor Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 35 Convent Drive, Bethesda, MD, 20892, USA

    Young Ho Suh

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  1. Akira Terashima
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Correspondence to John T. R. Isaac.

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Terashima, A., Suh, Y.H. & Isaac, J.T.R. The AMPA Receptor Subunit GluA1 is Required for CA1 Hippocampal Long-Term Potentiation but is not Essential for Synaptic Transmission. Neurochem Res 44, 549–561 (2019). https://doi.org/10.1007/s11064-017-2425-3

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  • DOI: https://doi.org/10.1007/s11064-017-2425-3

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