Presynaptic CLC-3 determines quantal size of inhibitory transmission in the hippocampus

Abstract

The authors report that the chloride channel CLC-3 colocalizes with the vesicular GABA transporter VGAT in the CA1 region of the hippocampus, where it affected Cl−-induced acidification of synaptic vesicles. Clcn3−/− animals showed a decrement in inhibitory transmission, suggesting a decrease in neurotransmitter loading of synaptic vesicles. The absence of the chloride channel CLC-3 in Clcn3−/− mice results in hippocampal degeneration with a distinct temporal-spatial sequence that resembles neuronal loss in temporal lobe epilepsy. We examined how the loss of CLC-3 might affect GABAergic synaptic transmission in the hippocampus. An electrophysiological study of synaptic function in hippocampal slices taken from Clcn3−/− mice before the onset of neurodegeneration revealed a substantial decrease in the amplitude and frequency of miniature inhibitory postsynaptic currents compared with those in wild-type slices. We found that CLC-3 colocalized with the vesicular GABA transporter VGAT in the CA1 region of the hippocampus. Acidification of inhibitory synaptic vesicles induced by Cl− showed a marked dependence on CLC-3 expression. The decrease in inhibitory transmission in Clcn3−/− mice suggests that the neurotransmitter loading of synaptic vesicles was reduced, which we attribute to defective vesicular acidification. Our observations extend the role of Cl− in inhibitory transmission from that of a postsynaptic permeant species to a presynaptic regulatory element.