Kuebler D, Zhang H, Ren X, Tanouye M A
Department of Molecular and Cell Biology, Division of Neurobiology, University of California, Berkeley, CA 94720, USA.
J Neurophysiol. 2001 Sep;86(3):1211-25. doi: 10.1152/jn.2001.86.3.1211.
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.
尽管癫痫疾病在人群中很常见，但这些缺陷的遗传和生理基础一直难以确定。虽然已经发现了许多导致癫痫易感性的遗传缺陷，但这些缺陷涉及不同的生物学过程，其中许多并非神经特异性的。所涉及基因的数量众多且性质各异，这使得理解癫痫疾病病因背后的复杂因素变得困难。研究已知基因突变对癫痫易感性的影响是一种可能富有成效的方法。这种方法在理解不同生理过程如何影响癫痫易感性以及识别新的治疗方法方面可能都有帮助。在本研究中，我们利用果蝇这一具有遗传易处理性的系统来识别抑制癫痫易感性的因素。特别令人感兴趣的是一组果蝇突变体，即对撞击敏感（BS）的突变体，它们比野生型更容易发生癫痫。BS表型类别至少包括八个基因，本研究中检测了其中三个基因，即bss、eas和sda。通过与其他特征明确的果蝇突变体产生双突变组合，BS突变体对于识别抑制癫痫易感性的遗传因素特别有用。我们发现，影响钠离子通道的突变体mle(napts)和para、钾离子通道的Sh以及电突触的shak - B(2)，可以抑制BS突变体中的癫痫发作。这是首次证明这些类型的突变能够抑制任何生物体中癫痫发作的发展。神经元兴奋性降低可能有助于抑制癫痫发作。最佳的抑制突变体mle(napts)导致巨纤维（GF）的刺激阈值升高，这与单个神经元兴奋性降低一致，而这可能是癫痫发作抑制的基础。对于其他一些与para和Sh(KS133)的双突变体，GF阈值没有变化，但GF频率降低也可能表明兴奋性降低。这些结果证明了果蝇作为研究癫痫易感性的模型系统的实用性，并确定了调节癫痫易感性的生理过程。
