Progressive NKCC1-dependent neuronal chloride accumulation during neonatal seizures.
Progressive NKCC1-dependent neuronal chloride accumulation during neonatal seizures.
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DOI：
10.1523/jneurosci.1769-10.2010
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发表时间：
2010-09-01
期刊：
影响因子：
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通讯作者：
Staley KJ
中科院分区：
文献类型：
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作者：
Dzhala VI;Kuchibhotla KV;Glykys JC;Kahle KT;Swiercz WB;Feng G;Kuner T;Augustine GJ;Bacskai BJ;Staley KJ
癫痫发作会诱发GABAA受体介导的逆转电位的兴奋性变化，这可能导致脑电图发作的顽固性，并妨碍广泛使用的GABAA能抗惊厥药（如苯巴比妥）的疗效。我们现在报道，在新生大鼠和表达Clomeleon的转基因小鼠制备的完整海马中，通过Clomeleon成像检测，反复发作会逐渐增加细胞内氯离子浓度（[Cl−]i），并通过动作电位频率和细胞内Ca2+瞬态检测，将GABAA受体激活的净效应从抑制逆转为兴奋。这些变化与癫痫样事件频率增加和苯巴比妥疗效降低有关。Na+-K+-2Cl−(NKCC1)共转运体阻滞剂布美他尼抑制癫痫发作诱导的神经元Cl−积累和随后的复发性癫痫发作的促进。我们的研究结果证明了一种新的机制，癫痫发作活动导致[Cl−]i积累，从而增加后续癫痫发作的可能性。这为新生儿癫痫发作的早期渐强阶段提供了一种潜在的机制。
Seizures induce excitatory shifts in the reversal potential for GABAA receptor-mediated responses, which may contribute to the intractability of electroencephalographic seizures and preclude the efficacy of widely-used GABAergic anticonvulsants such as phenobarbital. We now report that in intact hippocampi prepared from neonatal rats and transgenic mice expressing Clomeleon, recurrent seizures progressively increase the intracellular chloride concentration ([Cl−]i) assayed by Clomeleon imaging and invert the net effect of GABAA receptor activation from inhibition to excitation assayed by the frequency of action potentials and intracellular Ca2+ transients. These changes correlate with increasing frequency of seizure-like events and reduction in phenobarbital efficacy. The Na+-K+-2Cl− (NKCC1) co-transporter blocker bumetanide inhibited seizure-induced neuronal Cl− accumulation and the consequent facilitation of recurrent seizures. Our results demonstrate a novel mechanism by which seizure activity leads to [Cl−]i accumulation, thereby increasing the probability of subsequent seizures. This provides a potential mechanism for the early crescendo phase of neonatal seizures.