Tonic GABA inhibition in hippocampal dentate granule cells: its regulation and function in temporal lobe epilepsies

Abstract

Both human and experimental evidence strongly supports the view of brain region- and cell-specific changes in tonic GABA inhibition in temporal lobe epilepsies (TLE). This 'tonic' form of signalling is not time-locked to presynaptic action potentials, which depends upon detection of ambient GABA by extrasynaptic GABAA receptors (GABAA Rs). Extrasynaptic GABAA Rs have distinct physiological and pharmacological features, including high GABA-binding affinity and low desensitization and a variety of the specific subunit combinations (α4δ-,α6δ-,α5γ-,ε-containing receptors). These features closely contribute to the function of tonic GABA current, which is preserved properly or increased in dentate gyrus in models of TLE, even in the face of a loss of synaptic inhibition and inhibitory interneurones. Markedly reduced tonic GABA inhibition may facilitate an episode of epilepsy, while persistent elevated tonic inhibition may contribute to the onset of spontaneous recurrent seizures. In dentate granule cells, tonic GABA inhibition is positively modulated by endogenous neurosteroids and other factors, which undergo changes related to hormonal status after TLE. Tonic inhibition regulates neuronal excitability through its effects on membrane potential by both offsetting the threshold and reducing the frequency of action potentials and input resistance. Therefore, extrasynaptic GABAA Rs are expected to be the most important pharmacological targets in TLE. It is likely that both elevate the ambient GABA concentration and potentiate the tonic currents, contributing to the antiepileptic effects.