CLC-3 channels modulate excitatory synaptic transmission in hippocampal neurons

It is well established that ligand-gated chloride flux across the plasma membrane modulates neuronal excitability. We find that a voltage-dependent Cl- conductance increases neuronal excitability in immature rodents as well, enhancing the time course of NMDA receptor-mediated miniature excitatory postsynaptic potentials (mEPSPs). This Cl- conductance is activated by CaMKII, is electrophysiologically identical to the CaMKII-activated CLC-3 conductance in non-neuronal cells, and is absent in clc-3(-/-) mice. Systematically decreasing [CI-](i) to mimic postnatal [CI-](i) regulation progressively decreases the amplitude and decay time constant of spontaneous mEPSPs. This Cl--dependent change in synaptic strength is absent in clc-3(-/-) mice. Using surface biotinylation, immunohistochemistry, electron microscopy, and coimmuno-precipitation studies, we find that CLC-3 channels are localized on the plasma membrane, at postsynaptic sites, and in association with NMDA receptors. This is the first demonstration that a voltage-dependent chloride conductance modulates neuronal excitability. By increasing postsynaptic potentials in a Cl(-)dependent fashion, CLC-3 channels regulate neuronal excitability postsynaptically in immature neurons.