Endogenous polyamines regulate cortical neuronal excitability by blocking voltage-gated Na+ channels
Endogenous polyamines regulate cortical neuronal excitability by blocking voltage-gated Na+ channels
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DOI：
10.1073/pnas.0803464105
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发表时间：
2008-12-02
影响因子：
11.1
通讯作者：
Gutnick, Michael J.
中科院分区：
文献类型：
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作者：
Fleidervish, Ilya A.;Libman, Lior;Gutnick, Michael J.
由于新皮层神经元的可兴奋性取决于电压门控Na（+）通道的特性，调节这些特性的因素可以从根本上改变皮层回路的动力学。在这里，我们报道了一种新的神经调节机制，将Na（+）通道的可用性与大脑皮层中多胺（PAs）的代谢联系起来。通过单通道和全细胞记录，我们发现PA代谢产物，即普遍存在的脂肪族多阳离子精胺和亚精胺，是第5层锥体细胞中Na（+）通道的内源性阻滞剂。由于阻断是活性依赖的，它对不能迅速失活的Na（+）通道特别有效，因此是持续Na（+）电流的基础。在局部皮质回路水平上，PAS的药理学耗竭导致自发尖峰和超同步放电周期增加。我们的数据表明，PA水平的变化，无论是与正常大脑状态还是病理状态相关，都深刻地改变了Na（+）通道的可用性，从而塑造了单个神经元和新皮层回路的整合行为。
Because the excitable properties of neurons in the neocortex depend on the characteristics of voltage-gated Na(+) channels, factors which regulate those characteristics can fundamentally modify the dynamics of cortical circuits. Here, we report on a novel neuromodulatory mechanism that links the availability of Na(+) channels to metabolism of polyamines (PAs) in the cerebral cortex. Using single channel and whole-cell recordings, we found that products of PA metabolism, the ubiquitous aliphatic polycations spermine and spermidine, are endogenous blockers of Na(+) channels in layer 5 pyramidal cells. Because the blockade is activity-dependent, it is particularly effective against Na(+) channels which fail to inactivate rapidly and thus underlie the persistent Na(+) current. At the level of the local cortical circuit, pharmacological depletion of PAS led to increased spontaneous spiking and periods of hypersynchronous discharge. Our data suggest that changes in PA levels, whether associated with normal brain states or pathological conditions, profoundly modify Na(+) channel availability and thereby shape the integrative behavior of single neurons and neocortical circuits.