Deletion of TASK1 and TASK3 channels disrupts intrinsic excitability but does not abolish glucose or pH responses of orexin/hypocretin neurons
Deletion of TASK1 and TASK3 channels disrupts intrinsic excitability but does not abolish glucose or pH responses of orexin/hypocretin neurons
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DOI：
10.1111/j.1460-9568.2009.06789.x
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发表时间：
2009-07-01
影响因子：
3.4
通讯作者：
Burdakov, Denis
中科院分区：
文献类型：
--
作者：
Gonzalez, J. A.;Jensen, Lise T.;Burdakov, Denis
下丘脑下视丘分泌素/食欲素神经元的放电对正常的睡眠-觉醒转换至关重要，但其分子决定因素还不清楚。最近有人提出，（TWIK-related acid-sensitive potassium）channels [TASK 1（K（2 P）3.1）and/or TASK 3（K（2 P）9.1）]调节神经元放电，并可能有助于食欲素神经元对葡萄糖和pH的特异性反应。在这里，我们通过对来自TASK 1/TASK 3（K（2 P）9.1）脑切片中的食欲素神经元进行膜片钳记录来测试这些理论，这些神经元是通过靶向绿色荧光蛋白标记直接鉴定的。3只双敲除小鼠。TASK 1/3通道的缺失显著降低了食欲素细胞产生高频放电的能力。与兴奋性降低一致，来自敲除细胞的个体动作电位具有较低的上升速率、较高的阈值和更多的去极化后超极化。然而，来自TASK 1/3敲除小鼠的食欲素神经元保留了对葡萄糖和pH的典型反应，并且敲除动物显示出正常的食物预期运动活动。我们的研究结果支持了一个新的作用，在提高神经元的兴奋性和促进高频率的发射，但TASK 1/3亚基是不是必不可少的食欲素细胞对葡萄糖和pH值的反应。
The firing of hypothalamic hypocretin/orexin neurons is vital for normal sleep-wake transitions, but its molecular determinants are not well understood. It was recently proposed that TASK (TWIK-related acid-sensitive potassium) channels [TASK1 (K(2P)3.1) and/or TASK3 (K(2P)9.1)] regulate neuronal firing and may contribute to the specialized responses of orexin neurons to glucose and pH. Here we tested these theories by performing patch-clamp recordings from orexin neurons directly identified by targeted green fluorescent protein labelling in brain slices from TASK1/3 double-knockout mice. The deletion of TASK1/3 channels significantly reduced the ability of orexin cells to generate high-frequency firing. Consistent with reduced excitability, individual action potentials from knockout cells had lower rates of rise, higher thresholds and more depolarized after-hyperpolarizations. However, orexin neurons from TASK1/3 knockout mice retained typical responses to glucose and pH, and the knockout animals showed normal food-anticipatory locomotor activity. Our results support a novel role for TASK genes in enhancing neuronal excitability and promoting high-frequency firing, but suggest that TASK1/3 subunits are not essential for orexin cell responses to glucose and pH.