An RNAi screen identifies genes that regulate GABA synapses
An RNAi screen identifies genes that regulate GABA synapses
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DOI：
10.1016/j.neuron.2008.02.019
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发表时间：
2008-05-08
期刊：
影响因子：
16.2
通讯作者：
Kaplan, Joshua M.
中科院分区：
文献类型：
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作者：
Vashlishan, Amy B.;Madison, Jon M.;Kaplan, Joshua M.
GABA突触在电路发育和功能的许多方面发挥着关键作用。例如，扰乱GABA传递的情况被认为与癫痫有关。为了确定调节GABA传递的基因，我们进行了RNAi筛选，寻找其失活会增加线虫身体肌肉活动的基因，线虫身体肌肉接受GABA能运动神经元的直接输入。我们确定了90个基因，其中21个以前与癫痫综合征有关，这表明这一筛查已经有效地确定了癫痫的候选基因。兴奋性和抑制性突触的电生理记录和成像表明，有几个基因通过选择性地调节GABA传递来改变肌肉活动。特别是，我们确定了两条体液通路和几种蛋白激酶，它们调节GABA的传递，但对胆碱能神经肌肉接头的兴奋性传递几乎没有影响。我们的数据表明，这些保守的基因是调节GABA传递的信号通路的组成部分，因此可能在癫痫和其他认知或精神障碍中发挥作用。
GABA synapses play a critical role in many aspects of circuit development and function. For example, conditions that perturb GABA transmission have been implicated in epilepsy. To identify genes that regulate GABA transmission, we performed an RNAi screen for genes whose inactivation increases the activity of C. elegans body muscles, which receive direct input from GABAergic motor neurons. We identified 90 genes, 21 of which were previously implicated in seizure syndromes, suggesting that this screen has effectively identified candidate genes for epilepsy. Electrophysiological recordings and imaging of excitatory and inhibitory synapses indicate that several genes alter muscle activity by selectively regulating GABA transmission. In particular, we identify two humoral pathways and several protein kinases that modulate GABA transmission but have little effect on excitatory transmission at cholinergic neuromuscular junctions. Our data suggest these conserved genes are components of signaling pathways that regulate GABA transmission and consequently may play a role in epilepsy and other cognitive or psychiatric disorders.