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Calcineurin mediates synaptic scaling via synaptic trafficking of Ca2+-permeable AMPA receptors

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Kim, Seonil, Ziff, Edward B.·2014·PLoS Biology
DOI 10.1371/journal.pbio.1001900PMC PMC4077568
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Abstract

Homeostatic synaptic plasticity is a negative-feedback mechanism for compensating excessive excitation or inhibition of neuronal activity. When neuronal activity is chronically suppressed, neurons increase synaptic strength across all affected synapses via synaptic scaling. One mechanism for this change is alteration of synaptic AMPA receptor (AMPAR) accumulation. Although decreased intracellular Ca2+ levels caused by chronic inhibition of neuronal activity are believed to be an important trigger of synaptic scaling, the mechanism of Ca2+-mediated AMPAR-dependent synaptic scaling is not yet understood. Here, we use dissociated mouse cortical neurons and employ Ca2+ imaging, electrophysiological, cell biological, and biochemical approaches to describe a novel mechanism in which homeostasis of Ca2+ signaling modulates activity deprivation-induced synaptic scaling by three steps: (1) suppression of neuronal activity decreases somatic Ca2+ signals; (2) reduced activity of calcineurin, a Ca2+-dependent serine/threonine phosphatase, increases synaptic expression of Ca2+-permeable AMPARs (CPARs) by stabilizing GluA1 phosphorylation; and (3) Ca2+ influx via CPARs restores CREB phosphorylation as a homeostatic response by Ca2+-induced Ca2+ release from the ER. Therefore, we suggest that synaptic scaling not only maintains neuronal stability by increasing postsynaptic strength but also maintains nuclear Ca2+ signaling by synaptic expression of CPARs and ER Ca2+ propagation.

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  • Scaling-up involves an increase in phosphorylation of GluA1 S845, but not S831, and is completely blocked in neurons with GluA1 S845A knock-in mutations, but remains intact in GluA1 S831A mutant neurons.

    “Scaling-up involves an increase in phosphorylation of GluA1 S845, but not S831, and is completely blocked in neurons with GluA1 S845A knock-in mutations, but remains intact in GluA1 S831A mutant neurons (Diering et al., 2014, Kim and Ziff, 2014).”

    From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Kim and Ziff, 2014

    The Results section, “pGluA1(S845) Is Required for TTX-Induced Synaptic Scaling” (page unavailable), reports increased S845 phosphorylation after TTX treatment and says TTX could not induce scaling in neurons from GluA1 S845A knock-in mice. Our copy does not address whether S831 phosphorylation increases or whether scaling remains intact in S831A mutant neurons (searched: S831 phosphorylation, S831A mutant neurons). (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Kim, S., & Ziff, E. B.
Affiliations
NYU Langone Health (US)
Corresponding author
Ziff, Edward B.
ORCID
Venue
PLoS Biology
Publisher
Public Library of Science (PLoS)
Published
2014-07-01
Volume
12
Issue
7
Pages
e1001900
ISSN
  • 1544-9173 (ISSN-L)
  • 1545-7885
DOI
10.1371/journal.pbio.1001900
PMC
PMC4077568
OpenAlex
W2049294722
Cited by
114
References
9
Citations by year
2026: 7 · 2025: 7 · 2024: 9 · 2023: 7 · 2022: 6 · 2021: 11 · 2020: 10 · 2019: 8 · 2018: 17 · 2017: 6 · 2016: 15 · 2015: 11
FWCI
4.88
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Biology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • NYU Langone Medical Center
  • Johns Hopkins University
  • York University
  • National Institutes of Health (GCaMP5)
  • National Institute of Neurological Disorders and Stroke (R01NS061920)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
synaptic scaling, calcineurin, Ca2+-permeable AMPA receptors, homeostatic plasticity, GluA1 phosphorylation, CREB phosphorylation, activity deprivation, calcium signaling, cortical neurons, AMPA receptor trafficking
MeSH terms
Animals, Endoplasmic Reticulum, Homeostasis, Neuronal Plasticity, Tetrodotoxin, Receptors, AMPA, Calcineurin, Calcium Signaling, Protein Transport, Mice

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