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

PLoS Biol. 2014 Jul 1;12(7):e1001900. doi: 10.1371/journal.pbio.1001900. eCollection 2014 Jul.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcineurin / genetics
  • Calcineurin / physiology*
  • Calcium Signaling / physiology*
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / physiology
  • Homeostasis
  • Mice
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology*
  • Protein Transport / drug effects
  • Receptors, AMPA / metabolism*
  • Tetrodotoxin / pharmacology


  • Receptors, AMPA
  • Tetrodotoxin
  • Calcineurin
  • glutamate receptor ionotropic, AMPA 1