GABA_BReceptors Regulate Extrasynaptic GABA_AReceptors

Abstract

Tonic inhibitory GABA A receptor-mediated currents are observed in numerous cell types in the CNS, including thalamocortical neurons of the ventrobasal thalamus, dentate gyrus granule cells, and cerebellar granule cells. Here we show that in rat brain slices, activation of postsynaptic GABA B receptors enhances the magnitude of the tonic GABA A current recorded in these cell types via a pathway involving G i/o G proteins, adenylate cyclase, and cAMP-dependent protein kinase. Using a combination of pharmacology and knockout mice, we show that this pathway is independent of potassium channels or GABA transporters. Furthermore, the enhancement in tonic current is sufficient to significantly alter the excitability of thalamocortical neurons. These results demonstrate for the first time a postsynaptic crosstalk between GABA B and GABA A receptors.

GPCR Modulation of Extrasynapitic GABAA Receptors

“…The exact mechanism of this GABA B R-mediated enhancement of eGABA A R activity is unclear, though it seems to be independent on the synthesis of new channels since a maximal tonic GABA A current augmentation can be achieved within 5-10 min from the application of baclofen. Indeed, by diffusing drugs intracellularly, it could be demonstrated that the signalling pathway is dependent on PKA (Connelly et al 2013) (Fig. 7.1), indicating direct control of eGABA A Rs via phosphorylation, as has been demonstrated in expression systems (Tang et al 2010).…”

“…7.1), indicating direct control of eGABA A Rs via phosphorylation, as has been demonstrated in expression systems (Tang et al 2010). Interestingly, both studies (Connelly et al 2013;Tao et al 2013) reported that a GABA B antagonist reduced the tonic GABA A current even in the absence of activation by a GABA B agonist ( Fig. 7.1), indicating that at least in brain slices ambient GABA levels in thalamus, cerebellum and dentate gyrus are sufficient to activate this GABA B R-eGABA A interaction.…”

“…Moreover, increasing evidence is showing that a similar scenario is present in other brain areas. For instance, it seems that the activation of GABA B , D2 and 5-HT 2A/2C Rs preferentially modulates eGABA A R over sGABA A R-mediated conductance in the VB complex of the thalamus (Di Cavaccini et al 2012;Connelly et al 2013;Yague et al 2013), while mGlu, D2 and different 5-HTRs do affect both phasic and tonic inhibition in the dLGN (Munsch et al 2005;). This could be due to the different GPCRs synaptic localization and anatomical organization of dLGN and VB.…”

“…It does not result from changes in the release or uptake of GABA, since it is antagonized by direct intracellular infusion of G-protein antagonists into the postsynaptic neuron ( Fig. 7.1) (Connelly et al 2013;Tao et al 2013). The exact mechanism of this GABA B R-mediated enhancement of eGABA A R activity is unclear, though it seems to be independent on the synthesis of new channels since a maximal tonic GABA A current augmentation can be achieved within 5-10 min from the application of baclofen.…”

Characterization of GABAB-receptor mediated neurotransmission in the human cortex by paired-pulse TMS–EEG

“…Of note, the baclofen effect on LICI of the N100 was expressed ipsilateral, whilst the baclofen effect on LICI of the P180 was expressed contralateral to the stimulation. The mechanisms of baclofen-induced enhancement of LICI of these potentials are not clear, but may involve enhanced GABABergic neurotransmission in local inhibitory networks at the site of the stimulation, enhanced local GABABergic control of transcallosal inputs to the contralateral hemisphere (Irlbacher et al, 2007;Palmer et al, 2013), or a cross-talk between GABABRs and GABAARs as recently described within the thalamus (Connelly et al, 2013), resulting in disrupted thalamo-cortical communication important for propagation of later TEPs from the stimulated to the non-stimulated hemisphere.…”