The Contribution of Raised Intraneuronal Chloride to Epileptic Network Activity
The Contribution of Raised Intraneuronal Chloride to Epileptic Network Activity
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DOI：
10.1523/jneurosci.4105-14.2015
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发表时间：
2015-05-20
影响因子：
5.3
通讯作者：
Trevelyan, Andrew J.
中科院分区：
文献类型：
--
作者：
Alfonsa, Hannah;Merricks, Edward M.;Trevelyan, Andrew J.
抑制功能改变是癫痫病理学的一个重要方面。一个关键的概念是，如果神经元内氯化物升高，GABA能活性可以变得兴奋。然而，事实证明，很难将氯化物升高的作用与复杂网络现象（如癫痫病理学）中的其他促成因素分开。因此，我们问什么样的活动模式与氯离子失调，使新的使用盐视紫红质负载集群的小鼠锥体细胞人工与Cl-。盐视紫红质的短暂（1-10 s）激活引起GABA能逆转电位的显著正移，其与照明期间的电荷转移成比例，并且在成年新皮层锥体神经元中以τ = 8.0 +/-2.8 s的时间常数衰减。在网络水平上，E-GABA的这些正向变化产生了网络兴奋性的短暂上升，具有癫痫灶的许多独特特征，包括具有异相放电证据的高频振荡（Ibarz等人，2010年）。我们展示了这种放电模式是如何从平均细胞内Cl-水平的微小变化中产生的，在异质神经元群体中。然而，值得注意的是，即使对潜在的白色物质进行额外的电刺激，氯化物负荷本身也不会引发完全的发作事件。相反，当与低的亚癫痫水平的4-氨基吡啶组合时，盐视紫红质活化迅速诱导完全发作活性。这些结果表明，氯化物负荷在癫痫发作中至多具有抑制作用。我们的模拟还显示了氯化物负荷如何影响与即将发生的发作事件募集相关的动作电位时间抖动（Netoff和Schiff，2002）。
Altered inhibitory function is an important facet of epileptic pathology. A key concept is that GABAergic activity can become excitatory if intraneuronal chloride rises. However, it has proved difficult to separate the role of raised chloride from other contributory factors in complex network phenomena, such as epileptic pathology. Therefore, we asked what patterns of activity are associated with chloride dysregulation by making novel use of Halorhodopsin to load clusters of mouse pyramidal cells artificially with Cl-. Brief (1-10 s) activation of Halorhodopsin caused substantial positive shifts in the GABAergic reversal potential that were proportional to the charge transfer during the illumination and in adult neocortical pyramidal neurons decayed with a time constant of tau = 8.0 +/- 2.8s. At the network level, these positive shifts in E-GABA produced a transient rise in network excitability, with many distinctive features of epileptic foci, including high-frequency oscillations with evidence of out-of-phase firing (Ibarz et al., 2010). We show how such firing patterns can arise from quite small shifts in the mean intracellular Cl-level, within heterogeneous neuronal populations. Notably, however, chloride loading by itself did not trigger full ictal events, even with additional electrical stimulation to the underlying white matter. In contrast, when performed in combination with low, subepileptic levels of 4-aminopyridine, Halorhodopsin activation rapidly induced full ictal activity. These results suggest that chloride loading has at most an adjunctive role in ictogenesis. Our simulations also show how chloride loading can affect the jitter of action potential timing associated with imminent recruitment to an ictal event (Netoff and Schiff, 2002).