REST/NRSF-mediated intrinsic homeostasis protects neuronal networks from hyperexcitability
REST/NRSF-mediated intrinsic homeostasis protects neuronal networks from hyperexcitability
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DOI：
10.1038/emboj.2013.231
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发表时间：
2013-11-13
期刊：
影响因子：
11.4
通讯作者：
Baldelli, Pietro
中科院分区：
文献类型：
--
作者：
Pozzi, Davide;Lignani, Gabriele;Baldelli, Pietro
内在稳态使神经元回路通过调节神经元电压门控电导将活动水平维持在适当的范围内，但参与这一过程的信号通路在很大程度上是未知的。我们的特点是在培养的海马神经元的基础上激活的阻遏元件-1沉默转录因子/神经元限制性沉默因子（REST/NRSF）的持续电活动诱导的内在稳态的过程。我们发现，4-氨基吡啶诱导的活动过度增强REST/NRSF的表达，这反过来又减少了电压门控Na+通道的表达，从而降低了神经元Na+电流密度。这种机制在下调单细胞水平的放电活动中起着重要作用，在整个神经元网络中重建生理尖峰活动。相反，干扰REST/NRSF表达会损害这种稳态反应。我们的研究结果表明，REST/NRSF作为一个关键因素，连接神经元活动的内在稳态的激活和恢复生理水平的活动，在整个神经元网络。
Intrinsic homeostasis enables neuronal circuits to maintain activity levels within an appropriate range by modulating neuronal voltage-gated conductances, but the signalling pathways involved in this process are largely unknown. We characterized the process of intrinsic homeostasis induced by sustained electrical activity in cultured hippocampal neurons based on the activation of the Repressor Element-1 Silencing Transcription Factor/Neuron-Restrictive Silencer Factor (REST/NRSF). We showed that 4-aminopyridine-induced hyperactivity enhances the expression of REST/NRSF, which in turn, reduces the expression of voltage-gated Na+ channels, thereby decreasing the neuronal Na+ current density. This mechanism plays an important role in the down-regulation of the firing activity at the single-cell level, reestablishing a physiological spiking activity in the entire neuronal network. Conversely, interfering with REST/NRSF expression impaired this homeostatic response. Our results identify REST/NRSF as a critical factor linking neuronal activity to the activation of intrinsic homeostasis and restoring a physiological level of activity in the entire neuronal network.