NKCC1 and KCC2 prevent hyperexcitability in the mouse hippocampus
NKCC1 and KCC2 prevent hyperexcitability in the mouse hippocampus
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DOI：
10.1016/j.eplepsyres.2008.02.005
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发表时间：
2008-05-01
影响因子：
2.2
通讯作者：
Delpire, Eric
中科院分区：
文献类型：
--
作者：
Zhu, Lei;Polley, Nathan;Delpire, Eric
在中枢神经系统（CNS）出生后的发育过程中，GABA（A）受体对其激动剂的反应经历了从去极化到超极化的成熟过程。这种极性转换是由于神经元细胞内Cl浓度的发育性降低。在这里，我们表明，NKCC 1在P9-P13 CA 3锥体神经元的情况下，通过遗传操作或通过布美他尼抑制，导致细胞兴奋性的显着增加。此外，促惊厥剂4-氨基吡啶在NKCC 1缺失小鼠中诱导惊厥样事件，但在野生型小鼠中不诱导。在存在和不存在NKCC 1的情况下对蝇蕈醇反应的测量表明，Na-K-2Cl协同转运蛋白仅轻微影响P9-P13 CA 3主神经元中的细胞内Cl-。然而，在CA 3锥体神经元中观察到细胞内Cl-的大量增加，这表明P9-P13 CA 3锥体神经元在高突触活动期间缺乏强大的机制来调节细胞内Cl-。Cl-浓度的这种增加是网络驱动的和活性依赖性的，因为它被非NMDA谷氨酸受体拮抗剂DNQX阻断。我们还表明，表达的外向钾-氯转运蛋白，KCC 2，防止过度兴奋的发展，作为一个减少一半的KCC 2表达的结果在控制和4-AP条件下癫痫发作的易感性增加。(c)2008 Elsevier B. V.保留所有权利。
During postnatal development of the central nervous system (CNS), the response of GABA(A) receptors to its agonist undergoes maturation from depolarizing to hyperpolarizing. This switch in polarity is due to the developmental decrease of the intracellular Cl concentration in neurons. Here we show that absence of NKCC1 in P9-P13 CA3 pyramidal neurons, through genetic manipulation or through bumetanide inhibition, results in a significant increase in cell excitability. Furthermore, the pro-convulsant agent 4-aminopyridine induces seizure-like events in NKCC1-null mice but not in wild-type mice. Measurements of muscimol responses in the presence and absence of NKCC1 shows that the Na-K-2Cl cotransporter only marginally affects intracellular Cl- in P9-P13 CA3 principal neurons. However, large increases in intracellular Cl- are observed in CA3 pyramidal neurons following increased hyperexcitability, indicating that P9-P13 CA3 pyramidal neurons lack robust mechanisms to regulate intracellular Cl- during high synaptic activity. This increase in the Cl- concentration is network-driven and activity-dependent, as it is blocked by the non-NMDA glutamate receptor antagonist DNQX. We also show that expression of the outward K-Cl cotransporter, KCC2, prevents the development of hyperexcitability, as a reduction of KCC2 expression by half results in increased susceptibility to seizure under control and 4-AP conditions. (c) 2008 Elsevier B.V. All rights reserved.