Fibroblast growth factor homologous factors control neuronal excitability through modulation of voltage-gated sodium channels
Fibroblast growth factor homologous factors control neuronal excitability through modulation of voltage-gated sodium channels
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DOI：
10.1016/j.neuron.2007.07.006
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发表时间：
2007-08-02
期刊：
影响因子：
16.2
通讯作者：
D'Angelo, Egidio
中科院分区：
文献类型：
--
作者：
Goldfarb, Mitchell;Schoorlemmer, Jon;D'Angelo, Egidio
神经元通过称为“内在兴奋性”的过程将复杂的突触输入整合并编码为动作电位输出。在这里，我们报告了成纤维细胞生长因子同源因子（FHF）（电压门控钠通道结合蛋白家族）对此过程的重要贡献。 Fhf1(-/-)Fhf4(-/-) 小鼠患有严重的共济失调和其他神经缺陷。在小鼠小脑切片记录中，WT 颗粒神经元可以被诱导重复激发动作电位（类似于 60 Hz），而 Fhf1(-/-)Fhf4(-/-) 神经元通常仅激发一次，并且电压尖峰阈值升高。 Fhf1(-/-)Fhf4(-/-)颗粒神经元中的钠通道在膜电位负值更大时失活，失活更快，并且从失活状态恢复更慢。正如在颗粒细胞计算机模型中测试的那样，钠通道生理学的改变足以解释兴奋缺陷。这些发现提供了 Fhf4 突变引起的人类脊髓小脑共济失调的生理机制，并表明 FHF 在控制整个中枢神经系统兴奋性中发挥着广泛作用。
Neurons integrate and encode complex synaptic inputs into action potential outputs through a process termed "intrinsic excitability." Here, we report the essential contribution of fibroblast growth factor homologous factors (FHFs), a family of voltage-gated sodium channel binding proteins, to this process. Fhf1(-/-)Fhf4(-/-) mice suffer from severe ataxia and other neurological deficits. In mouse cerebellar slice recordings, WT granule neurons can be induced to fire action potentials repetitively (similar to 60 Hz), whereas Fhf1(-/-)Fhf4(-/-) neurons often fire only once and at an elevated voltage spike threshold. Sodium channels in Fhf1(-/-)Fhf4(-/-) granule neurons inactivate at more negative membrane potential, inactivate more rapidly, and are slower to recover from the inactivated state. Altered sodium channel physiology is sufficient to explain excitation deficits, as tested in a granule cell computer model. These findings offer a physiological mechanism underlying human spinocerebellar ataxia induced by Fhf4 mutation and suggest a broad role for FHFs in the control of excitability throughout the CNS.