Genetic suppression of seizure susceptibility in Drosophila
Genetic suppression of seizure susceptibility in Drosophila
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DOI：
10.1152/jn.2001.86.3.1211
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发表时间：
2001-09-01
影响因子：
2.5
通讯作者：
Tanouye, MA
中科院分区：
文献类型：
--
作者：
Kuebler, D;Zhang, HG;Tanouye, MA
尽管人类人群中癫痫发作障碍的频率很高，但这些缺陷的遗传和生理基础一直难以解决。虽然许多导致癫痫易感性的基因缺陷已被发现，但这些缺陷涉及不同的生物学过程，其中许多不是神经特异性的。涉及的基因数量众多，性质异质性，使得人们很难理解癫痫障碍病因的复杂因素。研究已知基因突变对癫痫易感性的影响是一种可能被证明是卓有成效的方法。这种方法可能有助于理解不同的生理过程如何影响癫痫易感性，并有助于确定新的治疗方法。在这项研究中，我们利用果蝇这一遗传易驯化系统来确定抑制癫痫敏感性的因素。特别令人感兴趣的是一组果蝇突变体，即爆炸敏感(BS)突变体，它们比野生型更容易癫痫发作。BS表型类至少包括8个基因，其中包括本研究中检测到的3个基因：bss、eas和sda。通过与其他特征良好的果蝇突变体产生双突变组合，BS突变体在识别抑制癫痫易感性的遗传因素方面特别有用。我们发现，影响Na+通道、MLE(NAPTS)和对、K+通道、Sh和电突触Shak-B-2的突变体可以抑制BS突变体的癫痫发作。这是第一次证明这些类型的突变可以抑制任何生物体中癫痫的发展。神经元兴奋性降低可能有助于癫痫的抑制。最好的抑制剂MLE(NAPTS)导致巨纤维(GF)刺激阈值增加，与单个神经元兴奋性的降低一致，这可能是抑制癫痫发作的基础。对于另一些带有对映体和Sh的双突变体(KS133)，没有出现GF阈值的变化，但兴奋性也可能通过GF跟随频率的减少来指示。这些结果表明，果蝇作为研究癫痫敏感性和识别改变癫痫敏感性的生理过程的模型系统是有用的。
Despite the frequency of seizure disorders in the human population, the genetic and physiological basis for these defects has been difficult to resolve. Although many genetic defects that cause seizure susceptibility have been identified, the defects involve disparate biological processes, many of which are not neural specific. The large number and heterogeneous nature of the genes involved makes it difficult to understand the complex factors underlying the etiology of seizure disorders. Examining the effect known genetic mutations have on seizure susceptibility is one approach that may prove fruitful. This approach may be helpful both in understanding how different physiological processes affect seizure susceptibility and in identifying novel therapeutic treatments. In this study, we have taken advantage of Drosophila, a genetically tractable system, to identify factors that suppress seizure susceptibility. Of particular interest has been a group of Drosophila mutants, the bang-sensitive (BS) mutants, which are much more susceptible to seizures than wild type. The BS phenotypic class includes at least eight genes, including three examined in this study, bss, eas, and sda. Through the generation of double-mutant combinations with other well-characterized Drosophila mutants, the BS mutants are particularly useful for identifying genetic factors that suppress susceptibility to seizures. We have found that mutants affecting Na+ channels, mle(napts) and para, K+ channels, Sh, and electrical synapses, shak-B-2, can suppress seizures in the BS mutants. This is the first demonstration that these types of mutations can suppress the development of seizures in any organism. Reduced neuronal excitability may contribute to seizure suppression. The best suppressor, mle(napts), causes an increased stimulation threshold for the giant fiber (GF) consistent with a reduction in single neuron excitability that could underlie suppression of seizures. For some other double mutants with para and Sh(KS133), there are no GF threshold changes, but reduced excitability may also be indicated by a reduction in GF following frequency. These results demonstrate the utility of Drosophila as a model system for studying seizure susceptibility and identify physiological processes that modify seizure susceptibility.