Patel, B; (2015) Functional properties of 4-PIOL at synaptic and extrasynaptic GABA-A receptors. Doctoral thesis , UCL (University College London).

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Abstract

GABAA receptors are the major inhibitory ligand-gated ion channels in the mammalian CNS. They mediate their physiological effects via two temporally and spatially distinct forms of signalling, denoted as phasic and tonic inhibition. These two forms of inhibition are mediated by distinct GABAA receptor subtypes, with phasic inhibition relying on the activation of synaptically-located γ2 subunit-containing receptors, and tonic inhibition requiring the activation of extrasynaptic receptors, predominantly thought to contain δ-subunits. The importance of tonic inhibition in regulating cell and network excitability has become increasingly apparent. Moreover, elevated tonic currents accompany neurological disorders such as stroke and absence epilepsy, suggesting that selectively reducing tonic inhibition might be therapeutically useful. Due to a lack of δ-selective antagonists, the theoretically predominant antagonist profile of the weak partial agonist, 4-PIOL, was studied as a potential mechanism for selectively reducing tonic inhibition. The functional effects of 4-PIOL were investigated firstly on whole-cell GABA-activated currents of several recombinant γ2- and δ-containing receptors expressed in HEK293 cells. As expected for a partial agonist, 4-PIOL exhibited both agonist- (at γ2-subunit GABAA receptors) and antagonist-type (at δ-subunit receptors) behaviours, depending on the GABA concentration. 4-PIOL was then assessed on tonic and phasic currents of cerebellar granule cells (CGCs), hippocampal pyramidal neurons and thalamic relay-neurons. In CGCs, 4-PIOL inhibited tonic currents, without affecting spontaneous inhibitory postsynaptic currents (sIPSCs); whereas in hippocampal and thalamic relay neurons, 4-PIOL enhanced, or reduced, tonic currents depending on the extrasynaptic GABA concentration, consistent with an action at extrasynaptic γ2-containing receptors. Moreover, 4-PIOL antagonised sIPSCs in these two brain regions, in accord with targeting presynaptic and postsynaptic GABAA receptors. In conclusion, the therapeutic potential of GABAA receptor partial agonists, such as 4-PIOL will be critically dependent on not only the ambient GABA concentration, but also on the relative expression of different GABAA receptor subtypes.

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