GABAB receptor subtypes differentially regulate thalamic spindle oscillations

Abstract

Following the discovery of GABA_B receptors by Norman Bowery and colleagues, cloning and biochemical efforts revealed that GABA_B receptors assemble multi-subunit complexes composed of principal and auxiliary subunits. The principal receptor subunits GABA_B1a, GABA_B1b and GABA_B2 form two heterodimeric GABA_B(1a,2) and GABA_B(1b,2) receptors that can associate with tetramers of auxiliary KCTD (K⁺ channel tetramerization domain) subunits. Experiments with subunit knock-out mice revealed that GABA_B(1b,2) receptors activate slow inhibitory postsynaptic currents (sIPSCs) while GABA_B(1a,2) receptors function as heteroreceptors and inhibit glutamate release. Both GABA_B(1a,2) and GABA_B(1b,2) receptors can serve as autoreceptors and inhibit GABA release. Auxiliary KCTD subunits regulate the duration of sIPSCs and scaffold effector channels at the receptor. GABA_B receptors are well known to contribute to thalamic spindle oscillations. Spindles are generated through alternating burst-firing in reciprocally connected glutamatergic thalamocortical relay (TCR) and GABAergic thalamic reticular nucleus (TRN) neurons. The available data implicate postsynaptic GABA_B receptors in TCR cells in the regulation of spindle frequency. We now used electrical or optogenetic activation of thalamic spindles and pharmacological experiments in acute slices of knock-out mice to study the impact of GABA_B(1a,2) and GABA_B(1b,2) receptors on spindle oscillations. We found that selectively GABA_B(1a,2) heteroreceptors at TCR to TRN cell synapses regulate oscillation strength, while GABA_B(1b,2) receptors control oscillation frequency. The auxiliary subunit KCTD16 influences both oscillation strength and frequency, supporting that KCTD16 regulates network activity through GABA_B(1a,2) and GABA_B(1b,2) receptors. This article is part of the "Special Issue Dedicated to Norman G. Bowery".

Keywords: Epilepsy; GPCR; KCTD12; KCTD16; Sleep.