Neuregulin 1 regulates excitability of fast-spiking neurons through Kv1.1 and acts in epilepsy
Neuregulin 1 regulates excitability of fast-spiking neurons through Kv1.1 and acts in epilepsy
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Neuregulin 1 通过 Kv1.1 调节快速放电神经元的兴奋性并在癫痫中发挥作用
DOI：
10.1038/nn.3006
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发表时间：
2012-02-01
影响因子：
25
通讯作者：
Li, Xiao-Ming
中科院分区：
文献类型：
--
作者：
Li, Ke-Xin;Lu, Ying-Mei;Li, Xiao-Ming
癫痫的发病机制中涉及快速尖峰，小清蛋白阳性（FS-PV）中间神经元的功能障碍。ErbB 4是神经调节蛋白1（Neuregulin 1，NRG 1）的一种重要受体，主要表达于这类中间神经元，最近的研究表明，小白蛋白中间神经元是成人脑内NRG 1-ErbB 4信号传导的主要靶点。因此，我们假设FS-PV中间神经元中NRG 1-ErbB 4信号转导的下调与癫痫有关。我们发现，NRG 1，通过其受体ErbB 4，增加FS-PV中间神经元的内在兴奋性。这种效应是通过增加近阈值反应性和降低电压阈值的动作电位通过Kv1.1，电压门控钾通道介导的。此外，在小白蛋白中间神经元中特异性缺失ErbB 4的小鼠对戊四唑和匹鲁卡品诱导的癫痫模型更敏感。外源性NRG 1可延迟癫痫发作，降低其发病率和分期。此外，ErbB 4的表达，而不是ErbB 2，在人类癫痫组织下调。总之，我们的研究结果表明，NRG 1-ErbB 4信号通过调节FS-PV中间神经元的兴奋性来促进人类癫痫。ErbB 4可能成为抗癫痫药物的新靶点。
Dysfunction of fast-spiking, parvalbumin-positive (FS-PV) interneurons is implicated in the pathogenesis of epilepsy. ErbB4, a key Neuregulin 1 (NRG1) receptor, is mainly expressed in this type of interneurons, and recent studies suggest that parvalbumin interneurons are a major target of NRG1-ErbB4 signaling in adult brain. Thus, we hypothesized that downregulation of NRG1-ErbB4 signaling in FS-PV interneurons is involved in epilepsy. We found that NRG1, through its receptor ErbB4, increased the intrinsic excitability of FS-PV interneurons. This effect was mediated by increasing the near-threshold responsiveness and decreasing the voltage threshold for action potentials through Kv1.1, a voltage-gated potassium channel. Furthermore, mice with specific deletion of ErbB4 in parvalbumin interneurons were more susceptible to pentylenetetrazole- and pilocarpine-induced models of epilepsy. Exogenous NRG1 delayed the onset of seizures and decreased their incidence and stage. Moreover, expression of ErbB4, but not ErbB2, was downregulated in human epileptogenic tissue. Together, our findings suggest that NRG1-ErbB4 signaling contributes to human epilepsy through regulating the excitability of FS-PV interneurons. ErbB4 may be a new target for anticonvulsant drugs in epilepsy.