CLC‐3 chloride channels moderate long‐term potentiation at Schaffer collateral–CA1 synapses

Key points The CLC‐3 chloride channel is expressed on postsynaptic membranes, where it is spatially and functionally linked to the NMDA receptor. CLC‐3 is phosphorylated by Ca 2+ /calmodulin kinase II. Loss of CLC‐3 expression or prevention of CLC‐3 phosphorylation/gating results in excessive induction of long‐term potentiation. Given that knockout of CLC‐3 results in hippocampal neurodegeneration, our results suggest that CLC‐3 gating may provide a protective limit on plasticity and Ca 2+ influx. Abstract The chloride channel CLC‐3 is expressed in the brain on synaptic vesicles and postsynaptic membranes. Although CLC‐3 is broadly expressed throughout the brain, the CLC‐3 knockout mouse shows complete, selective postnatal neurodegeneration of the hippocampus, suggesting a crucial role for the channel in maintaining normal brain function. CLC‐3 channels are functionally linked to NMDA receptors in the hippocampus; NMDA receptor‐dependent Ca 2+ entry, activation of Ca 2+ /calmodulin kinase II and subsequent gating of CLC‐3 link the channels via a Ca 2+ ‐mediated feedback loop. We demonstrate that loss of CLC‐3 at mature synapses increases long‐term potentiation from 135 ± 4% in the wild‐type slice preparation to 154 ± 7% above baseline ( P < 0.001) in the knockout; therefore, the contribution of CLC‐3 is to reduce synaptic potentiation by ∼40%. Using a decoy peptide representing the Ca 2+ /calmodulin kinase II phosphorylation site on CLC‐3, we show that phosphorylation of CLC‐3 is required for its regulatory function in long‐term potentiation. CLC‐3 is also expressed on synaptic vesicles; however, our data suggest functionally separable pre‐ and postsynaptic roles. Thus, CLC‐3 confers Cl − sensitivity to excitatory synapses, controls the magnitude of long‐term potentiation and may provide a protective limit on Ca 2+ influx.