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首页> 外文期刊>PLoS Biology >Calcineurin Mediates Synaptic Scaling Via Synaptic Trafficking of Ca2+-Permeable AMPA Receptors
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Calcineurin Mediates Synaptic Scaling Via Synaptic Trafficking of Ca2+-Permeable AMPA Receptors

机译：钙调神经磷酸酶通过Ca2 +渗透性AMPA受体的突触贩运介导突触缩放。

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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.
机译：稳态突触可塑性是一种负反馈机制，用于补偿过度兴奋或抑制神经元活动。当神经元活动被慢性抑制时，神经元通过突触缩放扩展所有受影响突触的突触强度。这种变化的一种机制是改变突触AMPA受体（AMPAR）的积累。尽管据信由神经活动的慢性抑制引起的细胞内Ca2 +水平降低是突触缩放的重要诱因，但Ca2 +介导的AMPAR依赖性突触缩放的机制尚不清楚。在这里，我们使用解离的小鼠皮质神经元，并采用Ca2 +成像，电生理，细胞生物学和生化方法来描述一种新的机制，其中Ca2 +信号的稳态通过三个步骤来调节活动剥夺诱导的突触缩放：（1）抑制神经元活动减少体细胞Ca2 +信号; （2）钙调神经磷酸酶（一种依赖Ca2 +的丝氨酸/苏氨酸磷酸酶）的活性降低，通过稳定GluA1磷酸化来增加Ca2 +渗透性AMPARs（CPARs）的突触表达; （3）通过CPAR的Ca2 +流入通过由Ca2 +诱导的ER从Ca2 +释放而恢复了CREB的磷酸化，作为体内稳态反应。因此，我们建议突触缩放不仅通过增加突触后强度来维持神经元的稳定性，而且还通过CPAR的突触表达和ER Ca2 +的传播来维持核Ca2 +信号传导。

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