Behavioural endophenotypes in mice lacking the auxiliary GABAB receptor 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 GABA_B receptors 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 GABA_B receptor 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 GABA_B receptor-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 GABA_B receptors contribute to the regulation of behaviours that could constitute endophenotypes for hyper-reactivity to aversive stimuli in neuropsychiatric disorders.

Keywords: Extinction; Fear learning; GABA(B); Gamma-aminobutyric acid; KCTD16; Memory; Neuropsychiatric disorders.