GABA receptor subtypes differentially regulate thalamic spindle oscillations.

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