title: The sodium-activated potassium channel Slack is required for optimal cognitive flexibility in mice.
abstract: Kcnt1 encoded sodium-activated potassium channels (Slack channels) are highly expressed throughout the brain where they modulate the firing patterns and general excitability of many types of neurons. Increasing evidence suggests that Slack channels may be important for higher brain functions such as cognition and normal intellectual development. In particular, recent findings have shown that human Slack mutations produce very severe intellectual disability and that Slack channels interact directly with the Fragile X mental retardation protein (FMRP), a protein that when missing or mutated results in Fragile X syndrome (FXS), the most common form of inherited intellectual disability and autism in humans. We have now analyzed a recently developed Kcnt1 null mouse model in several behavioral tasks to assess which aspects of memory and learning are dependent on Slack. We demonstrate that Slack deficiency results in mildly altered general locomotor activity, but normal working memory, reference memory, as well as cerebellar control of motor functions. In contrast, we find that Slack channels are required for cognitive flexibility, including reversal learning processes and the ability to adapt quickly to unfamiliar situations and environments. Our data reveal that hippocampal-dependent spatial learning capabilities require the proper function of Slack channels.
authors.affiliation: Pharmakologie, Toxikologie und Klinische Pharmazie, Institut für Pharmazie, 72076 Tübingen, Germany.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Bausch
authors.affiliation: Pharmakologie, Toxikologie und Klinische Pharmazie, Institut für Pharmazie, 72076 Tübingen, Germany.
authors.forename: Rebekka
authors.initials: R
authors.lastname: Dieter
authors.affiliation: Pharmakologie, Toxikologie und Klinische Pharmazie, Institut für Pharmazie, 72076 Tübingen, Germany.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Nann
authors.affiliation: Pharmakologie, Toxikologie und Klinische Pharmazie, Institut für Pharmazie, 72076 Tübingen, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Hausmann
authors.affiliation: Pharmakologie, Toxikologie und Klinische Pharmazie, Institut für Pharmazie, 72076 Tübingen, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Meyerdierks
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Leonard K
authors.initials: LK
authors.lastname: Kaczmarek
authors.affiliation: Pharmakologie, Toxikologie und Klinische Pharmazie, Institut für Pharmazie, 72076 Tübingen, Germany robert.lukowski@uni-tuebingen.de peter.ruth@uni-tuebingen.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Ruth
authors.affiliation: Pharmakologie, Toxikologie und Klinische Pharmazie, Institut für Pharmazie, 72076 Tübingen, Germany robert.lukowski@uni-tuebingen.de peter.ruth@uni-tuebingen.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Lukowski
mesh_terms: D000223:Adaptation, Psychological / Q000502:physiology*; D000818:Animals; D002531:Cerebellum / Q000378:metabolism; D003071:Cognition / Q000502:physiology*; D005106:Exploratory Behavior / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D008568:Memory / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009042:Motivation / Q000502:physiology; D009043:Motor Activity / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D000081033:Potassium Channels, Sodium-Activated; D012193:Reversal Learning / Q000502:physiology*
chemical_list: D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D000081033:Potassium Channels, Sodium-Activated; C479624:Slo2 protein, mouse