Homeostasis or channelopathy? Acquired cell type-specific ion channel changes in temporal lobe epilepsy and their antiepileptic potential.
Homeostasis or channelopathy? Acquired cell type-specific ion channel changes in temporal lobe epilepsy and their antiepileptic potential.
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DOI：
10.3389/fphys.2015.00168
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发表时间：
2015
影响因子：
4
通讯作者：
Laker D
中科院分区：
文献类型：
--
作者：
Wolfart J;Laker D
神经元不断适应其离子通道的表达和功能。例如，暴露于慢性兴奋性毒性，神经元稳态地降低其内在兴奋性。相反，“获得性通道病”假说表明，癫痫通道的特点在癫痫。我们回顾了不同癫痫条件下细胞类型特异性通道的改变，并讨论了作为抗癫痫药物（AEDs）靶点的通道进行稳态适应的潜力。大多数相关研究都是针对颞叶癫痫（TLE）进行的，TLE是一种广泛的AED难治性局灶性癫痫。接受癫痫手术的TLE患者经常显示海马硬化（HS），其与角氨亚区1锥体细胞（CA1 PC）的变性相关。虽然切除的人体组织提供了见解，但控制数据主要来自模拟TLE和其他癫痫不同方面的动物模型。大部分的细胞类型的具体信息可用于CA1 PC和齿状回颗粒细胞（DG GC）。在这两种细胞类型之间，可以观察到二分法：虽然DG GC获得降低内在兴奋性的特性（在TLE模型和HS患者中），但CA 1 PC发展出增加内在兴奋性的通道特性（仅在没有HS的TLE模型中）。然而，对这些和其他细胞类型的数据的彻底检查揭示了神经元内保护性和容许性内在可塑性的共存。这些机制出现差异调节，这取决于细胞类型和癫痫发作条件。有趣的是，在HS相关TLE期间DG GC中上调的相同通道分子似乎是未来AED和基因治疗的有希望的靶点。因此，GC提供了稳态离子通道适应的一个例子，其可以在设计新的抗癫痫策略时用作引物。
Neurons continuously adapt the expression and functionality of their ion channels. For example, exposed to chronic excitotoxicity, neurons homeostatically downscale their intrinsic excitability. In contrast, the “acquired channelopathy” hypothesis suggests that proepileptic channel characteristics develop during epilepsy. We review cell type-specific channel alterations under different epileptic conditions and discuss the potential of channels that undergo homeostatic adaptations, as targets for antiepileptic drugs (AEDs). Most of the relevant studies have been performed on temporal lobe epilepsy (TLE), a widespread AED-refractory, focal epilepsy. The TLE patients, who undergo epilepsy surgery, frequently display hippocampal sclerosis (HS), which is associated with degeneration of cornu ammonis subfield 1 pyramidal cells (CA1 PCs). Although the resected human tissue offers insights, controlled data largely stem from animal models simulating different aspects of TLE and other epilepsies. Most of the cell type-specific information is available for CA1 PCs and dentate gyrus granule cells (DG GCs). Between these two cell types, a dichotomy can be observed: while DG GCs acquire properties decreasing the intrinsic excitability (in TLE models and patients with HS), CA1 PCs develop channel characteristics increasing intrinsic excitability (in TLE models without HS only). However, thorough examination of data on these and other cell types reveals the coexistence of protective and permissive intrinsic plasticity within neurons. These mechanisms appear differentially regulated, depending on the cell type and seizure condition. Interestingly, the same channel molecules that are upregulated in DG GCs during HS-related TLE, appear as promising targets for future AEDs and gene therapies. Hence, GCs provide an example of homeostatic ion channel adaptation which can serve as a primer when designing novel anti-epileptic strategies.
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