Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis
Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis
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DOI：
10.1073/pnas.1510239112
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发表时间：
2015-10-20
影响因子：
11.1
通讯作者：
Chen, Lu
中科院分区：
文献类型：
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作者：
Arendt, Kristin L.;Zhang, Zhenjie;Chen, Lu
稳态突触可塑性是非赫布可塑性的一种形式，可维持网络的稳定性和信息处理的保真度，以响应网络和突触活动的长期扰动。长期阻断突触活动会降低神经元的静息 Ca2+ 水平，从而诱导视黄酸 (RA) 合成和 RA 依赖性稳态突触可塑性；然而，将降低的 Ca2+ 水平与 RA 合成联系起来的信号转导途径仍然未知。在这里，我们确定 Ca2+ 依赖性蛋白磷酸酶钙调神经磷酸酶 (CaN) 是 RA 合成和稳态突触可塑性的关键调节因子。长期抑制 CaN 活性会促进神经元中 RA 的合成，并导致兴奋性突触传递增加和抑制性突触传递减少。 CaN 抑制剂对突触传递的这些作用被 RA 合成的药理学抑制剂或 RA 受体 RAR α 的急性基因缺失所阻断。因此，CaN 作用于 RA 上游，在响应突触活动的门控 RA 信号通路中发挥着关键作用。此外，CaN 敲除神经元中不存在活动阻断诱导的稳态突触可塑性，这证明了 CaN 在 RA 依赖性稳态突触可塑性中的重要作用。有趣的是，在 GluA1 S831A 和 S845A 敲入小鼠中，CaN 抑制剂和 RA 诱导的突触传递调节是完整的，这表明 CaN 抑制剂或 RA 诱导的稳态突触可塑性不需要 GluA1 C 末端丝氨酸残基 S831 和 S845 的磷酸化。因此，我们的研究揭示了 CaN 在突触后信号传导中不可预见的作用，并将 CaN 定义为介导 RA 依赖性稳态突触可塑性的 Ca2+ 传感信号分子。
Homeostatic synaptic plasticity is a form of non-Hebbian plasticity that maintains stability of the network and fidelity for information processing in response to prolonged perturbation of network and synaptic activity. Prolonged blockade of synaptic activity decreases resting Ca2+ levels in neurons, thereby inducing retinoic acid (RA) synthesis and RA-dependent homeostatic synaptic plasticity; however, the signal transduction pathway that links reduced Ca2+-levels to RA synthesis remains unknown. Here we identify the Ca2+-dependent protein phosphatase calcineurin (CaN) as a key regulator for RA synthesis and homeostatic synaptic plasticity. Prolonged inhibition of CaN activity promotes RA synthesis in neurons, and leads to increased excitatory and decreased inhibitory synaptic transmission. These effects of CaN inhibitors on synaptic transmission are blocked by pharmacological inhibitors of RA synthesis or acute genetic deletion of the RA receptor RAR alpha. Thus, CaN, acting upstream of RA, plays a critical role in gating RA signaling pathway in response to synaptic activity. Moreover, activity blockade-induced homeostatic synaptic plasticity is absent in CaN knockout neurons, demonstrating the essential role of CaN in RA-dependent homeostatic synaptic plasticity. Interestingly, in GluA1 S831A and S845A knockin mice, CaN inhibitor-and RA-induced regulation of synaptic transmission is intact, suggesting that phosphorylation of GluA1 C-terminal serine residues S831 and S845 is not required for CaN inhibitor-or RA-induced homeostatic synaptic plasticity. Thus, our study uncovers an unforeseen role of CaN in postsynaptic signaling, and defines CaN as the Ca2+-sensing signaling molecule that mediates RA-dependent homeostatic synaptic plasticity.