ClC-2 contributes to tonic inhibition mediated by α5 subunit-containing GABAA receptor in experimental temporal lobe epilepsy

Temporal lobe epilepsy (TLE), characterized by spontaneous recurrent seizures, learning and memory impairments is associated with neurodegeneration, abnormal reorganization of the circuitry and loss of functional inhibition in hippocampus. In adult hippocampus, the GABAergic cells mediate the major inhibitory function of the principal neurons, promoting the Cl− entry through the GABAA receptor, whether through phasic (synaptic) or tonic (extrasynaptic) conductance. Aside from classical synaptic component, tonic GABAergic inhibition mediated by extrasynaptic GABAA receptor received increasing attention over the past years. There is growing evidence that tonic inhibition plays an important role in epilepsy, memory and cognition. Since GABAA receptor-mediated inhibition depends on the maintenance of intracellular Cl− concentration at low levels in mature neurons, a shift in Ecl is likely to participate in the generation and not merely a consequence of TLE. As we know, chloride channel-2 (ClC-2) is a member of the supergene family of voltage-gated chloride channels, it constitutes part of the background conductance and is involved in chloride extrusion. Here we show that ClC-2 were upregulated functionally in CA1 pyramidal cells in pilocarpine-treated rats, and that an observed increase in ClC-2 currents in CA1 pyramidal cells was reversed by L655,708, a specific antagonist of α5 subunit-containing GABAA receptor.

Graphical Abstract
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• Figure optionsDownload high-quality image (90 K)Download as PowerPoint slideHighlights▶We investigated the changes of ClC-2 in CA1 area in TLE model on rats. ▶We showed the functional increase of ClC-2 in CA1 pyramidal cells. ▶The changes are related to tonic inhibition mediated by α5 subunit-containing GABAAR.