Neuronal Inactivity Co-opts LTP Machinery to Drive Potassium Channel Splicing and Homeostatic Spike Widening.
Neuronal Inactivity Co-opts LTP Machinery to Drive Potassium Channel Splicing and Homeostatic Spike Widening.
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DOI：
10.1016/j.cell.2020.05.013
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发表时间：
2020-06-25
期刊：
影响因子：
64.5
通讯作者：
Tsien, Richard W.
中科院分区：
文献类型：
--
作者：
Li, Boxing;Suutari, Benjamin S.;Sun, Simon(e) D.;Luo, Zhengyi;Wei, Chuanchuan;Chenouard, Nicolas;Mandelberg, Nataniel J.;Zhang, Guoan;Wamsley, Brie;Tian, Guoling;Sanchez, Sandrine;You, Sikun;Huang, Lianyan;Neubert, Thomas A.;Fishell, Gordon;Tsien, Richard W.
神经放电特性的稳态对于稳定神经元回路很重要，但这种可塑性如何依赖于选择性剪接尚不清楚。在这里，我们报告说，慢性不活动稳态增加动作电位时程改变选择性剪接的BK通道，这需要核出口的剪接因子新星-2。不活动和Nova-2搬迁连接一个新的突触核信号通路，令人惊讶地调用机制类似于赫布可塑性：钙渗透AMPA受体上调，L型钙通道激活，增强脊柱钙瞬变，核转位的钙调蛋白穿梭，和核CaMKIV激活。这些发现不仅揭示了稳态和赫布可塑性之间的共性，而且还将突触传递和神经元兴奋性的稳态调节联系起来。信号级联为约25年前提出的经典自动调节反馈回路提供了一个完整的回路机制。神经环的每一个组成部分都与神经精神疾病有关。在长时程增强过程中，沉默神经元活动触发了与激活神经元类似的分子机制，证明了稳态尖峰调节的赫布机制。
Homeostasis of neural firing properties is important in stabilizing neuronal circuitry, but how such plasticity might depend on alternative splicing is not known. Here we report that chronic inactivity homeostatically increases action potential duration by changing alternative splicing of BK channels; this requires nuclear export of the splicing factor Nova-2. Inactivity and Nova-2 relocation were connected by a novel synapto-nuclear signaling pathway that surprisingly invoked mechanisms akin to Hebbian plasticity: Ca2+-permeable AMPA receptor upregulation, L-type Ca2+ channel activation, enhanced spine Ca2+ transients, nuclear translocation of a CaM shuttle, and nuclear CaMKIV activation. These findings not only uncover commonalities between homeostatic and Hebbian plasticity but also connect homeostatic regulation of synaptic transmission and neuronal excitability. The signaling cascade provides a full-loop mechanism for a classic autoregulatory feedback loop proposed ~25 years ago. Each element of the loop has been implicated previously in neuropsychiatric disease. Silencing neuronal activity triggers similar molecular mechanisms as activating neurons during long-term potentiation, demonstrating Hebbian mechanisms of homeostatic spike regulation.
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影响因子：
5.3
作者：
Buckanovich, RJ;Darnell, RB
通讯作者：
Darnell, RB
影响因子：
16.2
作者：
Geiger, JRP;Jonas, P
通讯作者：
Jonas, P
影响因子：
4.8
作者：
Edelman, AM;Mitchelhill, KI;Kemp, BE
通讯作者：
Kemp, BE
影响因子：
16.2
作者：
Deng PY;Rotman Z;Blundon JA;Cho Y;Cui J;Cavalli V;Zakharenko SS;Klyachko VA
通讯作者：
Klyachko VA
影响因子：
7.7
作者：
Eom T;Zhang C;Wang H;Lay K;Fak J;Noebels JL;Darnell RB
通讯作者：
Darnell RB