Abstract
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 α2 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.
Footnotes
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This work was supported in part by the German Research Council (Grant DFG WI 1951/1-2 to W.W.), by the Volkswagen Stiftung (Grant I/78 554 to W.W.), by the Academy of Finland (to E.R.K.), and by the Sigrid Juselius Foundation (to E.R.K.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.129544.
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ABBREVIATIONS: K2P, two-pore-domain background K+ channel; 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; KO, knockout; LOTW, loss of tail-withdrawal reflex; LORR, lossof righting reflex; ANOVA, analysis of variance; MAC, minimal alveolar concentration.
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↵1 Current affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre de Neurochimie, Strasbourg, France.
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↵2 Current affiliation: Instituto de Neurociencas de Alicante, Consejo Superior de Investigaciones Cientificas-Universidad Miguel Hernándes, Campus de San Juan, Sant Joan d'Alacant, Spain.
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↵3 Current affiliation: Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.
- Received August 1, 2007.
- Accepted September 14, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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