GABAB receptor subtypes differentially regulate thalamic spindle oscillations.

ABSTRACT

Following the discovery of GABAB receptors by Norman Bowery and colleagues, cloning and biochemical efforts revealed that GABAB receptors assemble multi-subunit complexes composed of principal and auxiliary subunits. The principal receptor subunits GABAB1a, GABAB1b and GABAB2 form two heterodimeric GABAB(1a,2) and GABAB(1b,2) receptors that can associate with tetramers of auxiliary KCTD (K+ channel tetramerization domain) subunits. Experiments with subunit knock-out mice revealed that GABAB(1b,2) receptors activate slow inhibitory postsynaptic currents (sIPSCs) while GABAB(1a,2) receptors function as heteroreceptors and inhibit glutamate release. Both GABAB(1a,2) and GABAB(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. GABAB 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 GABAB 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 GABAB(1a,2) and GABAB(1b,2) receptors on spindle oscillations. We found that selectively GABAB(1a,2) heteroreceptors at TCR to TRN cell synapses regulate oscillation strength, while GABAB(1b,2) receptors control oscillation frequency. The auxiliary subunit KCTD16 influences both oscillation strength and frequency, supporting that KCTD16 regulates network activity through GABAB(1a,2) and GABAB(1b,2) receptors. This article is part of the "Special Issue Dedicated to Norman G. Bowery".