Calcineurin mediates synaptic scaling via synaptic trafficking of Ca2+-permeable AMPA receptors.
Calcineurin mediates synaptic scaling via synaptic trafficking of Ca2+-permeable AMPA receptors.
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DOI：
10.1371/journal.pbio.1001900
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发表时间：
2014-07
期刊：
影响因子：
9.8
通讯作者：
Ziff EB
中科院分区：
文献类型：
--
作者：
Kim S;Ziff EB
Kim和Ziff研究了突触缩放的分子机制，表明神经元兴奋性的抑制减少了钙流入神经元，导致钙调磷酸酶活性降低。这导致钙渗透性AMPA受体的表面表达增加作为稳态响应。稳态突触可塑性是一种负反馈机制，用于补偿神经元活动的过度兴奋或抑制。当神经元活动长期受到抑制时，神经元通过突触缩放增加所有受影响突触的突触强度。这种变化的一个机制是突触AMPA受体（AMPAR）积累的改变。虽然由神经元活动的慢性抑制引起的细胞内Ca 2+水平降低被认为是突触缩放的重要触发因素，但Ca 2+介导的AMPAR依赖性突触缩放的机制尚未被理解。本研究利用分离的小鼠皮层神经元，采用Ca~（2+）成像、电生理、细胞生物学和生物化学方法，通过三个步骤描述了Ca~（2+）信号稳态调节活动剥夺诱导的突触缩放的新机制：（1）抑制神经元活动减少体细胞Ca~（2+）信号;（2）钙调神经磷酸酶（一种Ca 2+依赖性丝氨酸/苏氨酸磷酸酶）的活性降低，通过稳定GluA1磷酸化而增加Ca 2+渗透性AMPAR（CPARs）的突触表达;和（3）通过CPARs的Ca 2+内流恢复CREB磷酸化，作为Ca 2+诱导的Ca 2+从ER释放的稳态应答。因此，我们认为，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，而且还通过突触表达CPARs和ER Ca 2+传播来维持核Ca 2+信号传导。突触缩放是一种稳态可塑性的形式，它使突触（允许神经细胞进行通信的结构）的强度正常化，并由神经元活动的慢性抑制触发。虽然已经进行了广泛的研究，但这种突触适应的分子机制尚不清楚。使用培养的皮层神经元，我们表明，慢性抑制神经元的活动减少钙流入神经元，这反过来又降低了钙依赖性磷酸酶钙调神经磷酸酶的活性。这些变化导致含GluA1、钙可渗透的AMPA受体增加，AMPA受体介导突触处的通信。新插入的钙渗透性AMPA受体恢复钙电流，从而增强突触强度并恢复钙信号。我们还表明，钙调磷酸酶活性的抑制或激活是足以诱导或阻止突触缩放，分别，这表明钙调磷酸酶是一个重要的调解人的稳态突触可塑性。综上所述，我们的研究结果表明，突触缩放是一个稳态过程，不仅增强突触传递，但也保持在活动剥夺下的神经元钙信号。
Kim and Ziff examine the molecular mechanism of synaptic scaling, showing that inhibition of neuronal excitability reduces calcium influx into neurons, resulting in decreased calcineurin activity. This leads to increased surface expression of calcium-permeable AMPA receptors as a homeostatic response. 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. Synaptic scaling is a form of homeostatic plasticity that normalizes the strength of synapses (the structure that allows nerve cells to communicate) and is triggered by chronic inhibition of neuronal activity. Although extensive studies have been conducted, the molecular mechanism of this synaptic adaptation is not understood. Using cultured cortical neurons, we show that chronic inhibition of neuronal activity reduces calcium influx into neurons, which, in turn, decreases the activity of the calcium-dependent phosphatase calcineurin. These changes lead to an increase in GluA1-containing, calcium-permeable AMPA receptors, which mediate communication at the synapse. Newly inserted calcium-permeable AMPA receptors restore calcium currents, which enhance synaptic strength and recover calcium signaling. We also show that inhibition or activation of calcineurin activity is sufficient to induce or block synaptic scaling, respectively, suggesting that calcineurin is an important mediator of homeostatic synaptic plasticity. Taken together, our findings show that synaptic scaling is a homeostatic process that not only enhances synaptic transmission but also maintains calcium signaling in neurons under activity deprivation.
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影响因子：
3.4
作者：
Gong, Bo;Wang, Hansen;Zhuo, Min
通讯作者：
Zhuo, Min
DOI：
10.1523/jneurosci.3077-12.2012
发表时间：
2012-09-26
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Blackman MP;Djukic B;Nelson SB;Turrigiano GG
通讯作者：
Turrigiano GG
影响因子：
16.2
作者：
Goold, Carleton P.;Nicoll, Roger A.
通讯作者：
Nicoll, Roger A.
影响因子：
25
作者：
D'Amelio, Marcello;Cavallucci, Virve;Cecconi, Francesco
通讯作者：
Cecconi, Francesco
DOI：
10.1073/pnas.0706447105
发表时间：
2008-01-15
影响因子：
11.1
作者：
Hou, Qingming;Zhang, Dawei;Man, Heng-Ye
通讯作者：
Man, Heng-Ye