Functional properties and pharmacology of extrasynaptic GABA-A receptors

Abstract

The “ambient” GABA that is present in the extracellular space surrounding all neurons of the brain is believed to be capable of persistently activating high‐affinity extrasynaptic GABA-A receptors to generate a tonic membrane conductance. This generates a form of shunting inhibition that is capable of influencing cellular and network excitability. Extrasynaptic δ subunit-containing GABA-A receptors are known to generate this form of tonic inhibition in a number of defined brain regions and these are emerging as important clinical drug targets for the treatment of a number of neurological conditions. This thesis examines the functional and pharmacological properties of recombinant and native GABA-A receptors that allow them to function as ambient GABA detectors. Surprisingly, the data presented in this Thesis shows that the behaviour of these extrasynaptic GABA-A receptor populations is dramatically influenced by the steady-state GABA concentration they experience. For example, recombinant α4βδ and α6βδ receptor populations are shown to exhibit profound levels of desensitization in the presence of low ambient GABA levels that will limit their ability to respond to changes in ambient GABA. We also find that the action of certain sedative/hypnotic drugs on extrasynaptic GABA-A receptors expressed in cerebellar granule neurons is critically dependent upon the concentration of ambient GABA. For example, we show that the intravenous anaesthetic propofol will only enhance tonic inhibition when ambient GABA levels are below 100 nM. Similarly, we show that the GABA-A receptor agonist Gaboxadol is not capable of enhancing tonic inhibition when ambient GABA levels are high. In contrast to the behaviour of drugs like propofol and Gaboxadol, we find that neurosteroid enhancement of tonic inhibition will occur regardless of ambient GABA levels. This issue will be important when considering therapeutic strategies to target tonic inhibition in the treatment of neurological disorders. Furthermore, we show for the first time, that copper ions can potently block extrasynaptic GABA-A receptors, suggesting that copper may provide a means to selectively block tonic inhibition in the brain, and may even represent a novel source of extrasynaptic GABA-A receptor modulation in vivo.