Hekmat-Scafe Daria S, Lundy Miriam Y, Ranga Rakhee, Tanouye Mark A
Department of Environmental Science, Policy and Management, Division of Insect Biology, University of California, Berkeley, California 94720, USA.
J Neurosci. 2006 Aug 30;26(35):8943-54. doi: 10.1523/JNEUROSCI.4998-05.2006.
During a critical period in the developing mammalian brain, there is a major switch in the nature of GABAergic transmission from depolarizing and excitatory, the pattern of the neonatal brain, to hyperpolarizing and inhibitory, the pattern of the mature brain. This switch is believed to play a major role in determining neuronal connectivity via activity-dependent mechanisms. The GABAergic developmental switch may also be particularly vulnerable to dysfunction leading to seizure disorders. The developmental GABA switch is mediated primarily by KCC2, a neuronal K+/Cl- cotransporter that determines the intracellular concentration of Cl- and, hence, the reversal potential for GABA. Here, we report that kazachoc (kcc) mutations that reduce the level of the sole K+/Cl- cotransporter in the fruitfly Drosophila melanogaster render flies susceptible to epileptic-like seizures. Drosophila kcc protein is widely expressed in brain neuropil, and its level rises with developmental age. Young kcc mutant flies with low kcc levels display behavioral seizures and demonstrate a reduced threshold for seizures induced by electroconvulsive shock. The kcc mutation enhances a series of other Drosophila epilepsy mutations indicating functional interactions leading to seizure disorder. Both genetic and pharmacological experiments suggest that the increased seizure susceptibility of kcc flies occurs via excitatory GABAergic signaling. The kcc mutants provide an excellent model system in which to investigate how modulation of GABAergic signaling influences neuronal excitability and epileptogenesis.
在发育中的哺乳动物大脑的关键时期，GABA能传递的性质会发生重大转变，从新生儿大脑的去极化和兴奋性模式，转变为成熟大脑的超极化和抑制性模式。据信这种转变在通过活动依赖机制决定神经元连接方面起主要作用。GABA能发育转变也可能特别容易出现功能障碍，导致癫痫发作障碍。发育性GABA转变主要由KCC2介导，KCC2是一种神经元K+/Cl-共转运体，它决定细胞内Cl-浓度，进而决定GABA的反转电位。在此，我们报告，降低果蝇黑腹果蝇中唯一K+/Cl-共转运体水平的kazachoc（kcc）突变使果蝇易患癫痫样发作。果蝇kcc蛋白在脑髓质中广泛表达，其水平随发育年龄升高。kcc水平低的年轻kcc突变果蝇表现出行为性癫痫发作，并显示出电惊厥休克诱导癫痫发作的阈值降低。kcc突变增强了一系列其他果蝇癫痫突变，表明存在导致癫痫发作障碍的功能相互作用。遗传和药理学实验均表明，kcc果蝇癫痫易感性增加是通过兴奋性GABA能信号传导发生的。kcc突变体提供了一个极好的模型系统，用于研究GABA能信号传导的调节如何影响神经元兴奋性和癫痫发生。
