Linden Anni-Maija, Sandu Cristina, Aller M Isabel, Vekovischeva Olga Y, Rosenberg Per H, Wisden William, Korpi Esa R
Institute of Biomedicine, Pharmacology, University of Helsinki, POB 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland.
J Pharmacol Exp Ther. 2007 Dec;323(3):924-34. doi: 10.1124/jpet.107.129544. Epub 2007 Sep 17.
The TASK-3 channel is an acid-sensitive two-pore-domain K+ channel, widely expressed in the brain and probably involved in regulating numerous neuronal populations. Here, we characterized the behavioral and pharmacological phenotypes of TASK-3 knockout (KO) mice. Circadian locomotor activity measurements revealed that the nocturnal activity of the TASK-3 KO mice was increased by 38% (P < 0.01) compared with wild-type littermate controls, light phase activity being similar. Although TASK-3 channels are abundant in cerebellar granule cells, the KO mice performed as well as the wild-type mice in walking on a rotating rod or along a 1.2-cm-diameter beam. However, they fell more frequently from a narrower 0.8-cm beam. The KO mice showed impaired working memory in the spontaneous alternation task, with the alternation percentage being 62 +/- 3% for the wild-type mice and 48 +/- 4% (P < 0.05) for the KO mice. Likewise, during training for the Morris water-maze spatial memory task, the KO mice were slower to find the hidden platform, and in the probe trial, the female KO mice visited fewer times the platform quadrant than the male KO and wild-type mice. In pharmacological tests, the TASK-3 KO mice showed reduced sensitivity to the inhalation anesthetic halothane and the cannabinoid receptor agonist WIN55212-2 mesylate [(R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate] but unaltered responses to the alpha2 adrenoceptor agonist dexmedetomidine, the i.v. anesthetic propofol, the opioid receptor agonist morphine, and the local anesthetic lidocaine. Overall, our results suggest important contributions of TASK-3 channels in the neuronal circuits regulating circadian rhythms, cognitive functions, and mediating specific pharmacological effects.
TASK-3通道是一种酸敏感的双孔结构域钾通道，在大脑中广泛表达，可能参与调节众多神经元群体。在此，我们对TASK-3基因敲除（KO）小鼠的行为和药理学表型进行了表征。昼夜运动活动测量结果显示，与野生型同窝对照小鼠相比，TASK-3 KO小鼠的夜间活动增加了38%（P < 0.01），而光期活动相似。尽管TASK-3通道在小脑颗粒细胞中大量存在，但KO小鼠在旋转杆上行走或沿直径1.2厘米的横梁行走时表现与野生型小鼠一样好。然而，它们从更窄的0.8厘米横梁上掉落的频率更高。KO小鼠在自发交替任务中表现出工作记忆受损，野生型小鼠的交替百分比为62±3%，而KO小鼠为48±4%（P < 0.05）。同样，在莫里斯水迷宫空间记忆任务的训练过程中，KO小鼠找到隐藏平台的速度较慢，并且在探索试验中，雌性KO小鼠访问平台象限的次数少于雄性KO小鼠和野生型小鼠。在药理学测试中，TASK-3 KO小鼠对吸入麻醉剂氟烷和大麻素受体激动剂WIN55212-2甲磺酸盐[（R）-（+）-[2,3-二氢-5-甲基-3-（4-吗啉基甲基）吡咯并[1,2,3-de]-1,4-苯并恶嗪-6-基]-1-萘基甲酮甲磺酸盐]的敏感性降低，但对α2肾上腺素能受体激动剂右美托咪定、静脉麻醉剂丙泊酚、阿片受体激动剂吗啡和局部麻醉剂利多卡因的反应未改变。总体而言，我们的结果表明TASK-3通道在调节昼夜节律、认知功能以及介导特定药理作用的神经回路中具有重要作用。
