Calcineurin Mediates Synaptic Scaling Via Synaptic Trafficking of Ca(2+)-Permeable AMPA Receptors

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 Ca(2+) levels caused by chronic inhibition of neuronal activity are believed to be an important trigger of synaptic scaling, the mechanism of Ca(2+)-mediated AMPAR-dependent synaptic scaling is not yet understood. Here, we use dissociated mouse cortical neurons and employ Ca(2+) imaging, electrophysiological, cell biological, and biochemical approaches to describe a novel mechanism in which homeostasis of Ca(2+) signaling modulates activity deprivation-induced synaptic scaling by three steps: (1) suppression of neuronal activity decreases somatic Ca(2+) signals; (2) reduced activity of calcineurin, a Ca(2+)-dependent serine/threonine phosphatase, increases synaptic expression of Ca(2+)-permeable AMPARs (CPARs) by stabilizing GluA1 phosphorylation; and (3) Ca(2+) influx via CPARs restores CREB phosphorylation as a homeostatic response by Ca(2+)-induced Ca(2+) release from the ER. Therefore, we suggest that synaptic scaling not only maintains neuronal stability by increasing postsynaptic strength but also maintains nuclear Ca(2+) signaling by synaptic expression of CPARs and ER Ca(2+) propagation.