Cysteine String Protein-α Prevents Activity-Dependent Degeneration in GABAergic Synapses
Cysteine String Protein-α Prevents Activity-Dependent Degeneration in GABAergic Synapses
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DOI：
10.1523/jneurosci.0924-10.2010
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发表时间：
2010-05-26
影响因子：
5.3
通讯作者：
Fernandez-Chacon, Rafael
中科院分区：
文献类型：
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作者：
Garcia-Junco-Clemente, Pablo;Cantero, Gloria;Fernandez-Chacon, Rafael
神经递质的持续释放会给突触前蛋白质带来持续的负担，这可能会损害神经末梢功能。这种假设和可能保护高度活跃突触的分子机制值得研究。在缺乏突触前辅助伴侣半胱氨酸串蛋白-α (CSP-α) 的敲除小鼠的海马培养物中，我们观察到表达高活性突触结合蛋白 2 (Syt2) 的 GABA 能突触进行性变性，但令人惊讶的是谷氨酸能末端却没有。在 CSP-α 敲除小鼠中，在齿状回颗粒细胞上存在正常谷氨酸能突触的情况下，体内篮细胞末端的突触变性发生。与此一致的是，在这些小鼠的海马培养物中，由自发 GABA 释放引起的微型 IPSC 频率逐渐下降，而由谷氨酸自发释放引起的微型兴奋性 AMPA 受体介导电流 (mEPSC) 的频率正常。然而，mEPSC 幅度逐渐减小。值得注意的是，在缺乏 CSP-α 的培养物中长期阻断谷氨酸能传递基本上可以挽救表达 Syt2 的 GABA 能突触免于神经变性。这些发现表明，神经活动的升高会增加突触的脆弱性，并且 CSP-α 对于在生理高活性方案下维持突触前功能至关重要。
The continuous release of neurotransmitter could be seen to place a persistent burden on presynaptic proteins, one that could compromise nerve terminal function. This supposition and the molecular mechanisms that might protect highly active synapses merit investigation. In hippocampal cultures from knock-out mice lacking the presynaptic cochaperone cysteine string protein-alpha (CSP-alpha), we observe progressive degeneration of highly active synaptotagmin 2 (Syt2)-expressing GABAergic synapses, but surprisingly not of glutamatergic terminals. In CSP-alpha knock-out mice, synaptic degeneration of basket cell terminals occurs in vivo in the presence of normal glutamatergic synapses onto dentate gyrus granule cells. Consistent with this, in hippocampal cultures from these mice, the frequency of miniature IPSCs, caused by spontaneous GABA release, progressively declines, whereas the frequency of miniature excitatory AMPA receptor-mediated currents (mEPSCs), caused by spontaneous release of glutamate, is normal. However, the mEPSC amplitude progressively decreases. Remarkably, long-term block of glutamatergic transmission in cultures lacking CSP-alpha substantially rescues Syt2-expressing GABAergic synapses from neurodegeneration. These findings demonstrate that elevated neural activity increases synapse vulnerability and that CSP-alpha is essential to maintain presynaptic function under a physiologically high-activity regimen.