| Abstract |
Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain, is fundamental to brain function and implicated in the pathophysiology of several neuropsychiatric disorders. GABA activates G-protein-coupled GABAB receptors comprising principal GABAB1 and GABAB2 subunits as well as auxiliary KCTD8, 12, 12b and 16 subunits. TheKCTD12gene has been associated with bipolar disorder, major depressive disorder andschizophrenia. Here we compareKCTD12null mutant (KCTD12(-/-)) and heterozygous (KCTD12(+/-)) with wild-type (WT) littermate mice to determine whether lack of or reducedKCTD12expression leads to phenotypes that, extrapolating to human, could constitute endophenotypes for neuropsychiatric disorders with whichKCTD12is associated.KCTD12(- / -)小鼠表现出增加d fear learning but not increased memory of a discrete auditory-conditioned stimulus.KCTD12(+/-) mice showed increased activity during the inactive (light) phase of the circadian cycle relative to WT andKCTD12(-/-) mice. Electrophysiological recordings from hippocampal slices, a region of highKCTD12expression, revealed an increased intrinsic excitability of pyramidal neurons inKCTD12(-/-) andKCTD12(+/-) mice. This is the first direct evidence for involvement ofKCTD12in determining phenotypes of emotionality, behavioral activity and neuronal excitability. This study provides empirical support for the polymorphism and expression evidence thatKCTD12confers risk for and is associated with neuropsychiatric disorders. |