NKCC1 transporter facilitates seizures in the developing brain
NKCC1 transporter facilitates seizures in the developing brain
复制标题
DOI：
10.1038/nm1301
复制
发表时间：
2005-11-01
期刊：
影响因子：
82.9
通讯作者：
Staley, KJ
中科院分区：
文献类型：
--
作者：
Dzhala, VI;Talos, DM;Staley, KJ
在发育过程中，由于细胞内Cl-水平升高和去极化Cl-平衡电位（E-Cl），Cl-渗透性GABA（A）受体（GABA（A）-R）的激活使神经元兴奋。GABA成为抑制性的净向外神经元运输的Cl-的发展，在一个尾-吻的进展。与这种尾部-喙部发育模式一致，GABA能抗惊厥化合物抑制新生儿癫痫发作的运动表现，但不抑制皮质癫痫发作活动。Na ~+-K ~+-2Cl（-）协同转运体（NKCC 1）促进Cl ~-在神经元内的蓄积。NKCC 1阻断剂布美他尼在未成熟神经元中转移EC 1阴性，抑制体外海马切片中的癫痫样活动，并在体内减弱新生大鼠的电图癫痫发作。布美他尼在GABAA-R拮抗剂荷包牡丹碱的存在下没有作用，在NKCC 1基因敲除小鼠的脑切片中也没有作用。NKCC 1表达水平与人和大鼠皮质中Cl-挤压转运蛋白（KCC 2）的表达表明，围产期人皮质中的Cl-转运与大鼠中的一样不成熟。我们的研究结果提供的证据表明，NKCC 1促进癫痫发作在发育中的大脑，并表明布美他尼应该是有用的新生儿癫痫发作的治疗。
During development, activation of Cl--permeable GABA(A) receptors ( GABA(A)-R) excites neurons as a result of elevated intracellular Cl- levels and a depolarized Cl- equilibrium potential ( E-Cl). GABA becomes inhibitory as net outward neuronal transport of Cl- develops in a caudal- rostral progression. In line with this caudal- rostral developmental pattern, GABAergic anticonvulsant compounds inhibit motor manifestations of neonatal seizures but not cortical seizure activity. The Na+-K+-2Cl(-) cotransporter ( NKCC1) facilitates the accumulation of Cl- in neurons. The NKCC1 blocker bumetanide shifted ECl negative in immature neurons, suppressed epileptiform activity in hippocampal slices in vitro and attenuated electrographic seizures in neonatal rats in vivo. Bumetanide had no effect in the presence of the GABAA-R antagonist bicuculline, nor in brain slices from NKCC1-knockout mice. NKCC1 expression level versus expression of the Cl--extruding transporter ( KCC2) in human and rat cortex showed that Cl- transport in perinatal human cortex is as immature as in the rat. Our results provide evidence that NKCC1 facilitates seizures in the developing brain and indicate that bumetanide should be useful in the treatment of neonatal seizures.