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Enhanced synaptic plasticity in mice with phosphomimetic mutation of the GluA1 AMPA receptor

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Makino, Yuichi, Johnson, Richard C., Yu, Yilin, Takamiya, Kogo, Huganir, Richard L.·2011·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1105261108PMC PMC3100939
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Abstract

Phosphorylation of the GluA1 subunit of AMPA receptors has been proposed to regulate receptor trafficking and synaptic transmission and plasticity. However, it remains unclear whether GluA1 phosphorylation is permissive or sufficient for enacting these functional changes. Here we investigate the role of GluA1 phosphorylation at S831 and S845 residues in the hippocampus through the analyses of GluA1 S831D/S845D phosphomimetic knock-in mice. S831D/S845D mice showed normal total and surface expression and subcellular localization of GluA1 as well as intact basal synaptic transmission. In addition, theta-burst stimulation, a protocol that was sufficient to induce robust long-term potentiation (LTP) in WT mice, resulted in LTP of similar magnitude in S831D/S845D mice. However, S831D/S845D mice showed LTP induced with 10-Hz stimulation, a protocol that is weaker than theta-burst stimulation and was not sufficient to induce LTP in WT mice. Moreover, S831D/S845D mice exhibited LTP induced with spike-timing–dependent plasticity (STDP) protocol at a long pre-post interval that was subthreshold for WT mice, although a suprathreshold STDP protocol at a short pre-post interval resulted in similarly robust LTP for WT and S831D/S845D mice. These results indicate that phosphorylation of GluA1 at S831 and S845 is sufficient to lower the threshold for LTP induction, increasing the probability of synaptic plasticity.

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  • The AMPAR code predicts that under certain conditions the PSD slots will have biased affinity towards certain AMPAR variants, for example phosphorylated GluA1-containing receptors during noradrenaline facilitated hippocampal LTP.

    “The AMPAR code predicts that under certain conditions the PSD slots will have biased affinity towards certain AMPAR variants, for example phosphorylated GluA1-containing receptors during noradrenaline facilitated hippocampal LTP (Makino et al., 2011, Hu et al., 2007).”

    From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Makino et al., 2011

    In the Discussion model, Makino et al. propose that GluA1 phosphorylation may increase interactions with scaffolding proteins in a perisynaptic microdomain, making the receptors easier to insert into synapses. The Results also show that norepinephrine phosphorylates GluA1 in hippocampal slices and permits LTP after weak stimulation. The paper does not establish that PSD slots have biased affinity for phosphorylated GluA1-containing receptors; its proposed scaffolding mechanism is qualified and perisynaptic. (LLM, conf=0.84)

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  • The study did not see enhanced induction or expression of LTP in ΔPIX mice using weaker stimuli of 50 Hz or 10 Hz that enhance potentiation in conditional CaN knockout mice and GluA1 S831,845D mice.

    “We did not see enhanced induction or expression of LTP in ΔPIX mice using weaker stimuli of 50 Hz or 10 Hz that enhance potentiation in conditional CaN knockout mice (Zeng et al., 2001) and GluA1 S831,845D mice that mimic constitutive GluA1 phosphorylation”

    From AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca<sup>2+</sup>-Permeable AMPA Receptors (2012) · cites this paper as Makino et al., 2011

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Authors
Makino, Y., Johnson, R. C., Yu, Y., Takamiya, K., & Huganir, R. L.
Affiliations
  • Howard Hughes Medical Institute (US)
  • University of Miyazaki (JP)
Corresponding author
Huganir, Richard L.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2011-05-02
Volume
108
Issue
20
Pages
8450-8455
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1105261108
PMC
PMC3100939
OpenAlex
W1991789257
Cited by
77
References
4
Citations by year
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FWCI
3.58
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institutes of Health (NS036715)
  • Japan Society for the Promotion of Science (22300122)
  • National Institute of Mental Health (R01MH064856)
  • National Institute of Neurological Disorders and Stroke (R01NS036715)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
GluR1, AMPA receptors, receptor phosphorylation, phosphomimetic mutations, long-term potentiation, spike-timing-dependent plasticity, synaptic plasticity, theta burst stimulation, hippocampus
MeSH terms
Animals, Hippocampus, Mutation, Synaptic Transmission, Neuronal Plasticity, Phosphorylation, Long-Term Potentiation, Receptors, AMPA, Mice

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