title: Behavioural endophenotypes in mice lacking the auxiliary GABABreceptor subunit KCTD16.
abstract: Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is implicated in the pathophysiology of a number of neuropsychiatric disorders. The GABABreceptors are G-protein coupled receptors consisting of principle subunits and auxiliary potassium channel tetramerization domain (KCTD) subunits. The KCTD subunits 8, 12, 12b and 16 are cytosolic proteins that determine the kinetics of the GABABreceptor response. Previously, we demonstrated that Kctd12 null mutant mice (Kctd12-/-) exhibit increased auditory fear learning and that Kctd12+/-mice show altered circadian activity, as well as increased intrinsic excitability in hippocampal pyramidal neurons. KCTD16 has been demonstrated to influence neuronal excitability by regulating GABABreceptor-mediated gating of postsynaptic ion channels. In the present study we investigated for behavioural endophenotypes in Kctd16-/-and Kctd16+/-mice. Compared with wild-type (WT) littermates, auditory and contextual fear conditioning were normal in both Kctd16-/-and Kctd16+/-mice. When fear memory was tested on the following day, Kctd16-/-mice exhibited less extinction of auditory fear memory relative to WT and Kctd16+/-mice, as well as more contextual fear memory relative to WT and, in particular, Kctd16+/-mice. Relative to WT, both Kctd16+/-and Kctd16-/-mice exhibited normal circadian activity. This study adds to the evidence that auxillary KCTD subunits of GABABreceptors contribute to the regulation of behaviours that could constitute endophenotypes for hyper-reactivity to aversive stimuli in neuropsychiatric disorders.
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders (PLaTRAD), Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland; Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland.
authors.forename: Flurin
authors.initials: F
authors.lastname: Cathomas
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders (PLaTRAD), Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland.
authors.forename: Hannes
authors.initials: H
authors.lastname: Sigrist
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders (PLaTRAD), Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Schmid
authors.affiliation: Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland; Neuroscience Center, University and ETH Zurich, Switzerland.
authors.forename: Erich
authors.initials: E
authors.lastname: Seifritz
authors.affiliation: Department of Biomedicine, Institute of Physiology, University of Basel, Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Gassmann
authors.affiliation: Department of Biomedicine, Institute of Physiology, University of Basel, Basel, Switzerland. Electronic address: bernhard.bettler@unibas.ch.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders (PLaTRAD), Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland; Neuroscience Center, University and ETH Zurich, Switzerland. Electronic address: christopher.pryce@bli.uzh.ch.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Pryce
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D002940:Circadian Rhythm / Q000235:genetics; D003214:Conditioning, Classical / Q000502:physiology*; D058068:Endophenotypes; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear / Q000502:physiology; D005260:Female; D005838:Genotype; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015221:Potassium Channels / Q000172:deficiency* / Q000235:genetics
chemical_list: D015221:Potassium Channels
keywords: Extinction; Fear learning; GABA(B); Gamma-aminobutyric acid; KCTD16; Memory; Neuropsychiatric disorders