title: TASK-3 as a potential antidepressant target.
abstract: Modulation of TASK-3 (Kcnk9) potassium channels affect neurotransmitter release in thalamocortical centers and other sleep-related nuclei having the capacity to regulate arousal cycles and REM sleep changes associated with mood disorders and antidepressant action. Circumstantial evidence from this and previous studies suggest the potential for TASK-3 to be a novel antidepressant therapeutic target; TASK-3 knock-out mice display augmented circadian amplitude and exhibit sleep architecture characterized by suppressed REM activity. Detailed analysis of locomotor activity indicates that the amplitudes of activity bout duration and bout number are augmented in TASK-3 mutants well beyond that seen in wildtypes, findings substantiated by amplitude increases in body temperature and EEG recordings of sleep stage bouts. Polysomnographic analysis of TASK-3 mutants reveals increases in nocturnal active wake and suppressed REM sleep time while increased slow wave sleep typifies the inactive phase, findings that have implications for the cognitive impact of reduced TASK-3 activity. In direct measures of their resistance to despair behavior, TASK-3 knock-outs displayed significant decreases in immobility relative to wildtype controls in both tail suspension and forced swim tests. Treatment of wildtype animals with the antidepressant Fluoxetine markedly reduced REM sleep, while leaving active wake and slow wave sleep relatively intact. Remarkably, these effects were absent in TASK-3 mutants indicating that TASK-3 is either directly involved in the mechanism of this drug's action, or participates in parallel pathways that achieve the same effect. Together, these results support the TASK-3 channel to act as a therapeutic target for antidepressant action.
authors: Department of Neuroscience, Merck Research Laboratories, West Point, PA, USA. anthony_gotter@merck.com
authors: Anthony L
authors: AL
authors: Gotter
authors: Vincent P
authors: VP
authors: Santarelli
authors: Scott M
authors: SM
authors: Doran
authors: Pamela L
authors: PL
authors: Tannenbaum
authors: Richard L
authors: RL
authors: Kraus
authors: Thomas W
authors: TW
authors: Rosahl
authors: Hamid
authors: H
authors: Meziane
authors: Marina
authors: M
authors: Montial
authors: Duane R
authors: DR
authors: Reiss
authors: Keith
authors: K
authors: Wessner
authors: Alexander
authors: A
authors: McCampbell
authors: Joanne
authors: J
authors: Stevens
authors: Joseph I
authors: JI
authors: Brunner
authors: Steven V
authors: SV
authors: Fox
authors: Victor N
authors: VN
authors: Uebele
authors: Douglas A
authors: DA
authors: Bayliss
authors: Christopher J
authors: CJ
authors: Winrow
authors: John J
authors: JJ
authors: Renger
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D001143:Arousal / Q000502:physiology*; D001522:Behavior, Animal / Q000502:physiology; D002940:Circadian Rhythm / Q000502:physiology*; D003863:Depression / Q000188:drug therapy / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005473:Fluoxetine / Q000494:pharmacology*; D008297:Male; D016555:Matched-Pair Analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D010641:Phenotype; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012895:Sleep, REM / Q000502:physiology*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D015221:Potassium Channels; C511784:TASK3 protein, mouse; D005473:Fluoxetine