ClC-2 voltage-gated channels constitute part of the background conductance and assist chloride extrusion

The function of voltage-gated chloride channels in neurons is essentially unknown. The voltage-gated chloride channel ClC-2 mediates a chloride current in pyramidal cells of the hippocampus. We directly show that ClC-2 assists chloride extrusion after high chloride load. Furthermore, the loss of this chloride channel leads to a dramatic increase of the input resistance of CA1 pyramidal cells, making these cells more excitable. Surprisingly, basal synaptic transmission, as judged from recordings of field EPSPs, was decreased. This difference was eliminated when GABAergic inhibition was blocked. Recordings from hippocampal interneurons revealed ClC-2-mediated currents in a subset of these cells. An observed increase in GABAergic inhibition could thus be explained by an increase in the excitability of interneurons, caused by the loss of ClC-2. Together, we suggest a dual role for ClC-2 in neurons, providing an additional efflux pathway for chloride and constituting a substantial part of the background conductance, which regulates excitability. In ClC-2 knock-out mice, an increased inhibition seemingly balances the hyperexcitability of the network and thereby prevents epilepsy.