CLC-3 chloride channels moderate long-term potentiation at Schaffer collateralCA1 synapses
CLC-3 chloride channels moderate long-term potentiation at Schaffer collateralCA1 synapses
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DOI：
10.1113/jphysiol.2012.243485
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发表时间：
2013-02-01
影响因子：
5.5
通讯作者：
Nelson, Deborah J.
中科院分区：
文献类型：
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作者：
Farmer, Laurel M.;Le, Brandy N.;Nelson, Deborah J.
氯离子通道 CLC-3 在大脑中的突触小泡和突触后膜上表达。尽管 CLC-3 在整个大脑中广泛表达，但 CLC-3 敲除小鼠显示出完全的、选择性的出生后海马神经变性，表明该通道在维持正常大脑功能中发挥着至关重要的作用。 CLC-3 通道在功能上与海马中的 NMDA 受体相关； NMDA 受体依赖性 Ca2+ 进入、Ca2+/钙调蛋白激酶 II 的激活以及随后的 CLC-3 门控通过 Ca2+ 介导的反馈环路将通道连接起来。我们证明，成熟突触处 CLC-3 的缺失使长期增强作用从野生型切片制备中的 135 +/- 4% 增加到敲除中高于基线的 154 +/- 7% (P < 0.001)；因此，CLC-3 的贡献是将突触增强降低约 40%。使用代表 CLC-3 上 Ca2+/钙调蛋白激酶 II 磷酸化位点的诱饵肽，我们表明 CLC-3 的磷酸化是其长期增强的调节功能所必需的。 CLC-3 也在突触小泡上表达；然而，我们的数据表明突触前和突触后的作用在功能上是可分离的。因此，CLC-3 赋予 Cl 对兴奋性突触的敏感性，控制长期增强的幅度，并可能对 Ca2+ 流入提供保护性限制。
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 Ca2+ entry, activation of Ca2+/calmodulin kinase II and subsequent gating of CLC-3 link the channels via a Ca2+-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 approximate to 40%. Using a decoy peptide representing the Ca2+/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 Ca2+ influx.