KCTD8 and KCTD12 Facilitate Axonal Expression of GABA Receptors in Habenula Cholinergic Neurons.

GABA receptors in habenula cholinergic neurons mediate strong presynaptic excitation and control aversive memory expression. K channel tetramerization domain (KCTD) proteins are key interacting partners of GABA receptors; it remains unclear whether and how KCTDs contribute to GABA excitatory signaling. Here, we show that KCTD8 and KCTD12 in these neurons facilitate the GABA receptors expression in axonal terminals and contribute to presynaptic excitation by GABA receptors. Genetically knocking out or , but not other combinations of the three isoforms, substantially reduced GABA receptors-mediated potentiation of glutamate release and presynaptic Ca entry in response to axonal stimulation, whereas they had no effect on GABA-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 GABA expression within the axonal terminals but not the somata. Overexpressing either KCTD8 or KCTD12 in the triple knock-out mice reversed the changes in axonal GABA expression and presynaptic excitation. In mice lacking the KCTDs, aversion-predicting cues produced stronger neuronal activation in the interpeduncular nucleus, and the infusion of GABA agonist 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 GABA receptors, facilitating their presynaptic signaling, and modulating aversion-related memory processes. GABA receptors 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 GABA receptors. 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 GABA receptors 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.