Synergistic Roles of GABAA Receptors and SK Channels in Regulating Thalamocortical Oscillations
Synergistic Roles of GABAA Receptors and SK Channels in Regulating Thalamocortical Oscillations
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DOI：
10.1152/jn.91158.2008
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发表时间：
2009-07-01
影响因子：
2.5
通讯作者：
Huguenard, John R.
中科院分区：
文献类型：
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作者：
Kleiman-Weiner, Max;Beenhakker, Mark P.;Huguenard, John R.
Kleiman-Weiner M，Beenhakker MP，Segal WA，Huguenard JR. GABA A受体和SK通道在调节丘脑皮层振荡中的协同作用J Neurophysiol 102：203-213，2009.首次发表于2009年4月22日; doi：10.1152/jn.91158.2008。在大脑的生理和病理状态下，可以观察到整个皮层的节律性振荡。丘脑产生睡眠梭形振荡和失神癫痫特征性的棘波放电。关于这些振荡的机制，人们已经从体外脑切片制备中了解到了很多。一个广泛使用的模型，以了解癫痫样振荡背后的失神癫痫涉及应用荷包牡丹碱甲碘（BMI）的大脑切片含有丘脑。BMI是一种众所周知的GABA A受体阻滞剂，先前已发现其也可阻断小电导钙激活钾（SK）通道。在这里，我们报告说，在BMI应用程序中观察到的强大的癫痫样振荡依赖于GABA A受体和SK通道拮抗作用协同。无论是应用印防己毒素，一种选择性GABA A受体拮抗剂，也不应用apamin，一种选择性SK通道拮抗剂，单独产生高度同步，持久的振荡与BMI应用过程中观察到的那些。然而，部分封锁SK通道subnanomolar浓度的蜂毒结合印防己毒素充分复制BMI振荡。我们发现，在细胞水平上，apamin增强网状核（RT）神经元的内在兴奋性，但对中继神经元没有影响。这项工作表明，RT兴奋性调节SK通道可以影响丘脑皮质网络的兴奋性，并可能照亮失神癫痫的可能的药物治疗。最后，我们的研究结果表明，单个神经元的内在属性的变化和电路水平的变化可以鲁棒地调制这些振荡。
Kleiman-Weiner M, Beenhakker MP, Segal WA, Huguenard JR. Synergistic roles of GABA A receptors and SK channels in regulating thalamocortical oscillations. J Neurophysiol 102: 203-213, 2009. First published April 22, 2009; doi: 10.1152/jn.91158.2008. Rhythmic oscillations throughout the cortex are observed during physiological and pathological states of the brain. The thalamus generates sleep spindle oscillations and spike-wave discharges characteristic of absence epilepsy. Much has been learned regarding the mechanisms underlying these oscillations from in vitro brain slice preparations. One widely used model to understand the epileptiform oscillations underlying absence epilepsy involves application of bicuculline methiodide (BMI) to brain slices containing the thalamus. BMI is a well-known GABA A receptor blocker that has previously been discovered to also block small-conductance, calcium-activated potassium (SK) channels. Here we report that the robust epileptiform oscillations observed during BMI application rely synergistically on both GABA A receptor and SK channel antagonism. Neither application of picrotoxin, a selective GABA A receptor antagonist, nor application of apamin, a selective SK channel antagonist, alone yielded the highly synchronized, long-lasting oscillations comparable to those observed during BMI application. However, partial blockade of SK channels by subnanomolar concentrations of apamin combined with picrotoxin sufficiently replicated BMI oscillations. We found that, at the cellular level, apamin enhanced the intrinsic excitability of reticular nucleus (RT) neurons but had no effect on relay neurons. This work suggests that regulation of RT excitability by SK channels can influence the excitability of thalamocortical networks and may illuminate possible pharmacological treatments for absence epilepsy. Finally, our results suggest that changes in the intrinsic properties of individual neurons and changes at the circuit level can robustly modulate these oscillations.