GABAB receptor subtypes differentially regulate thalamic spindle oscillations

Abstract

a b s t r a c tFollowing 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 þ 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.

The meaning of EEG indicators of loss of consciousness during anaesthesia and coma.

“…Baclofen dramatically increases the power of synchronized slow waves in rats during NREM sleep in the 1.5-6.5 and 9.5-21.5 frequency bands (Hodor et al, 2015), which includes delta and alpha, but also beta and theta and overlaps with the potentiated effects on the EEG by general anaesthetics. However, GABAB receptor only partially modulates thalamic spindles (Ulrich et al, 2018), consistent with the idea of a convergent non-GABA, ACh muscarinic receptor-related generation of spindles.…”

Sleep Spindles: Mechanisms and Functions

“…Additionally, extrasynaptic GABA B receptors contribute to phasic inhibition during TRN burst discharge (323), but their contribution appears to be species dependent (51,323). Presynaptic GABA B homoreceptors on TRN-TC terminals (360) and heteroceptors at the TC-TRN terminals play modulatory roles (607). A tonic form of inhibition through extrasynaptic ␦-containing GABA A receptors keeps the resting membrane potential of TC neurons hyperpolarized and facilitates rebound bursting in response to phasic inhibition (125).…”

Neurophysiological alterations in the nucleus reuniens of a mouse model of Alzheimer's disease

“…GABAB receptors are widely expressed throughout the mouse thalamus. When activated at synapses the resultant post-synaptic hyperpolarization can reliably generate rebound burst firing in thalamic relay neurons (Ulrich et al, 2018). A radioligand binding analysis reported many baclofen sensitive GABA binding sites in Re (Hosford et al, 1995), and the same study provided evidence of directionally opposed outcomes of GABAB receptor agonism and antagonism on spike and wave discharges in the lethargic mouse model of absence seizures.…”