title: Calcineurin mediates synaptic scaling via synaptic trafficking of Ca2+-permeable AMPA receptors.
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.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, New York, United States of America.
authors.forename: Seonil
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, New York, United States of America.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Ziff
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology; D006706:Homeostasis; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D021381:Protein Transport / Q000187:drug effects; D018091:Receptors, AMPA / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D019703:Calcineurin; D018091:Receptors, AMPA; D013779:Tetrodotoxin