KCTD8 and KCTD12 Facilitate Axonal Expression of GABABReceptors in Habenula Cholinergic Neurons

Abstract

GABABreceptors in habenula cholinergic neurons mediate strong presynaptic excitation and control aversive memory expression. K+channel tetramerization domain (KCTD) proteins are key interacting partners of GABABreceptors; it remains unclear whether and how KCTDs contribute to GABABexcitatory signaling. Here, we show that KCTD8 and KCTD12 in these neurons facilitate the GABABreceptors expression in axonal terminals and contribute to presynaptic excitation by GABABreceptors. Genetically knocking outKCTD8/12/16orKCTD8/12, but not other combinations of the threeKCTDisoforms, substantially reduced GABABreceptors–mediated potentiation of glutamate release and presynaptic Ca2+entry in response to axonal stimulation, whereas they had no effect on GABAB-mediated inhibition in the somata of cholinergic neurons within the habenulo–interpeduncular pathway in mice of either sex. The physiological phenotypes were associated with a significant decrease in the GABABexpression within the axonal terminals but not the somata. Overexpressing either KCTD8 or KCTD12 in theKCTD8/12/16triple knock-out mice reversed the changes in axonal GABABexpression and presynaptic excitation. In mice lacking the KCTDs, aversion-predicting cues produced stronger neuronal activation in the interpeduncular nucleus, and the infusion of GABABagonist in this nucleus produced a weaker effect on fear extinction. Collectively, our results reveal isoform-specific roles of KCTD proteins in enriching the axonal expression of GABABreceptors, facilitating their presynaptic signaling, and modulating aversion-related memory processes.SIGNIFICANCE STATEMENTGABABreceptors represent the principal inhibitory neurotransmitter receptor, but they mediate strong presynaptic excitation in the habenulo–interpeduncular pathway and modulate aversion memory expression. KCTD proteins are integral constituents of GABABreceptors. By analyzing the physiological, neuroanatomical, and behavioral phenotypes of multiple KCTD knock-out mouse lines, we show that KCTD8 and KCTD12 facilitate the axonal expression and hence presynaptic excitation of GABABreceptors in habenula cholinergic neurons and control cued-aversion memory formation and expression in the habenulo–interpeduncular pathway. These results expand the physiological and behavioral functions of KCTDs in modulating the brain neural circuits.