Nav1.6a Is Required for Normal Activation of Motor Circuits Normally Excited by Tactile Stimulation
Nav1.6a Is Required for Normal Activation of Motor Circuits Normally Excited by Tactile Stimulation
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DOI：
10.1002/dneu.2079
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发表时间：
2010-06-01
影响因子：
3
通讯作者：
Kuwada, John Y.
中科院分区：
文献类型：
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作者：
Low, Sean E.;Zhou, Weibin;Kuwada, John Y.
对斑马鱼马达突变体的筛选发现了两个隐性突变的非互补等位基因，它们被命名为非活性(NAVN(Mi89)和NAV(Mi130))。在发育的前3天，NAY胚胎表现出减少的自发和触摸诱发的逃避行为。遗传作图表明，编码Na(V)1.6a(Scn8aa)的基因可能是NAY的候选基因。随后从NaY的两个等位基因克隆scn8aa，发现了Na(V)1.6a的两个错义突变，当异源分析时，这两个错义突变消除了通道活性。此外，注射编码野生型setz8aa的RNA挽救了NAV突变表型，表明scn8aa是NAY的致病基因。对触觉诱发逃逸回路的在体电生理分析表明，突变体的机械感觉神经元的电压依赖性内向电流减少，但它们能够发射动作电位。此外，突变体的触觉刺激激活了机械感觉神经元下游的一些神经元，但未能激活游泳运动回路，这与最初的逃逸收缩而不是游泳的行为反应一致。因此，突变型机械感觉神经元似乎对触觉刺激有反应，但不能启动游泳。有趣的是，假想的游泳可以在药理学上启动，这表明突变体中存在一个游泳回路。这些结果表明，Na(V)1.6a是触觉诱导的游泳运动网络激活所必需的。(C)2010Wiley期刊公司开发神经生物学70：508-522.2010
A screen for zebrafish motor mutants identified two noncomplementing alleles of a recessive mutation that were named non-active (navn(mi89) and nav(mi130)). nay embryos displayed diminished spontaneous and touch-evoked escape behaviors during the first 3 days of development. Genetic mapping identified the gene encoding Na(v)1.6a (scn8aa) as a potential candidate for nay. Subsequent cloning of scn8aa from the two alleles of nay uncovered two missense mutations in Na(v)1.6a that eliminated channel activity when assayed heterologously. Furthermore, the injection of RNA encoding wild-type setz8aa rescued the nav mutant phenotype indicating that scn8aa was the causative gene of nay. In-vivo electrophysiological analysis of the touch-evoked escape circuit indicated that voltage-dependent inward current was decreased in mechanosensory neurons in mutants, but they were able to fire action potentials. Furthermore, tactile stimulation of mutants activated some neurons downstream of mechanosensory neurons but failed to activate the swim locomotor circuit in accord with the behavioral response of initial escape contractions but no swimming. Thus, mutant mechanosensory neurons appeared to respond to tactile stimulation but failed to initiate swimming. Interestingly fictive swimming could be initiated pharmacologically suggesting that a swim circuit was present in mutants. These results suggested that Na(v)1.6a was required for touch-induced activation of the swim locomotor network. (C) 2010 Wiley Periodicals, Inc. Develop Neurobiol 70: 508-522.2010