TASK-3 knockout mice exhibit exaggerated nocturnal activity, impairments in cognitive functions, and reduced sensitivity to inhalation anesthetics.
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.
Linden
Anni-Maija
AM
Institute of Biomedicine, Pharmacology, University of Helsinki, POB 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland. anni-maija.linden@helsinki.fi
Sandu
Cristina
C
Aller
M Isabel
MI
Vekovischeva
Olga Y
OY
Rosenberg
Per H
PH
Wisden
William
W
Korpi
Esa R
ER
D018685:Anesthetics, Inhalation / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000502:physiology; D002940:Circadian Rhythm / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005260:Female; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*
D018685:Anesthetics, Inhalation; D015221:Potassium Channels; C511784:TASK3 protein, mouse