{"title":"共生细菌加剧果蝇电压门控钠通道突变体的癫痫样表型","authors":"Patrick Lansdon, Junko Kasuya, Toshihiro Kitamoto","doi":"10.1111/gbb.70000","DOIUrl":null,"url":null,"abstract":"<p>Mutations in voltage-gated sodium (Na<sub>v</sub>) channels, which are essential for generating and propagating action potentials, can lead to serious neurological disorders, such as epilepsy. However, disease-causing Na<sub>v</sub> channel mutations do not always result in severe symptoms, suggesting that the disease conditions are significantly affected by other genetic factors and various environmental exposures, collectively known as the “exposome”. Notably, recent research emphasizes the pivotal role of commensal bacteria in neural development and function. Although these bacteria typically benefit the nervous system under normal conditions, their impact during pathological states remains largely unknown. Here, we investigated the influence of commensal microbes on seizure-like phenotypes exhibited by <i>para</i><sup><i>Shu</i></sup>—a gain-of-function mutant of the <i>Drosophila</i> Na<sub>v</sub> channel gene, <i>paralytic</i>. Remarkably, the elimination of endogenous bacteria considerably ameliorated neurological impairments in <i>para</i><sup><i>Shu</i></sup>. Consistently, reintroducing bacteria, specifically from the <i>Lactobacillus</i> or <i>Acetobacter</i> genera, heightened the phenotypic severity in the bacteria-deprived mutants. These findings posit that particular native bacteria contribute to the severity of seizure-like phenotypes in <i>para</i><sup><i>Shu</i></sup>. We further uncovered that treating <i>para</i><sup><i>Shu</i></sup> with antibiotics boosted Nrf2 signaling in the gut, and that global Nrf2 activation mirrored the effects of removing bacteria from <i>para</i><sup><i>Shu</i></sup>. This raises the possibility that the removal of commensal bacteria suppresses the seizure-like manifestations through augmented antioxidant responses. Since bacterial removal during development was critical for suppression of adult <i>para</i><sup><i>Shu</i></sup> phenotypes, our research sets the stage for subsequent studies, aiming to elucidate the interplay between commensal bacteria and the developing nervous system in conditions predisposed to the hyperexcitable nervous system.</p>","PeriodicalId":50426,"journal":{"name":"Genes Brain and Behavior","volume":"23 5","pages":""},"PeriodicalIF":2.4000,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373613/pdf/","citationCount":"0","resultStr":"{\"title\":\"Commensal bacteria exacerbate seizure-like phenotypes in Drosophila voltage-gated sodium channel mutants\",\"authors\":\"Patrick Lansdon, Junko Kasuya, Toshihiro Kitamoto\",\"doi\":\"10.1111/gbb.70000\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Mutations in voltage-gated sodium (Na<sub>v</sub>) channels, which are essential for generating and propagating action potentials, can lead to serious neurological disorders, such as epilepsy. 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Consistently, reintroducing bacteria, specifically from the <i>Lactobacillus</i> or <i>Acetobacter</i> genera, heightened the phenotypic severity in the bacteria-deprived mutants. These findings posit that particular native bacteria contribute to the severity of seizure-like phenotypes in <i>para</i><sup><i>Shu</i></sup>. We further uncovered that treating <i>para</i><sup><i>Shu</i></sup> with antibiotics boosted Nrf2 signaling in the gut, and that global Nrf2 activation mirrored the effects of removing bacteria from <i>para</i><sup><i>Shu</i></sup>. This raises the possibility that the removal of commensal bacteria suppresses the seizure-like manifestations through augmented antioxidant responses. 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引用次数: 0
摘要
电压门控钠(Nav)通道对产生和传播动作电位至关重要,其突变可导致严重的神经系统疾病,如癫痫。然而,致病的 Nav 通道突变并不总是导致严重的症状,这表明疾病状况受到其他遗传因素和各种环境暴露(统称为 "暴露组")的显著影响。值得注意的是,最近的研究强调了共生细菌在神经发育和功能中的关键作用。虽然这些细菌在正常情况下通常有益于神经系统,但它们在病理状态下的影响在很大程度上仍不为人所知。在这里,我们研究了共生微生物对果蝇 Nav 通道基因麻痹功能增益突变体 paraShu 所表现出的癫痫样表型的影响。值得注意的是,消除内源细菌大大改善了paraShu的神经损伤。一致的是,重新引入细菌,特别是乳酸杆菌属或醋酸纤维菌属的细菌,会加重缺菌突变体的表型严重性。这些研究结果表明,特定的本地细菌会导致paraShu癫痫样表型的严重程度。我们进一步发现,用抗生素治疗paraShu会促进肠道中的Nrf2信号转导,而Nrf2的全面激活反映了从paraShu中移除细菌的效果。这就提出了一种可能性,即清除共生细菌可以通过增强抗氧化反应来抑制癫痫发作样表现。由于在发育过程中清除细菌对于抑制成体paraShu表型至关重要,我们的研究为后续研究奠定了基础,旨在阐明在易导致神经系统过度兴奋的条件下,共生细菌与发育中的神经系统之间的相互作用。
Mutations in voltage-gated sodium (Nav) channels, which are essential for generating and propagating action potentials, can lead to serious neurological disorders, such as epilepsy. However, disease-causing Nav channel mutations do not always result in severe symptoms, suggesting that the disease conditions are significantly affected by other genetic factors and various environmental exposures, collectively known as the “exposome”. Notably, recent research emphasizes the pivotal role of commensal bacteria in neural development and function. Although these bacteria typically benefit the nervous system under normal conditions, their impact during pathological states remains largely unknown. Here, we investigated the influence of commensal microbes on seizure-like phenotypes exhibited by paraShu—a gain-of-function mutant of the Drosophila Nav channel gene, paralytic. Remarkably, the elimination of endogenous bacteria considerably ameliorated neurological impairments in paraShu. Consistently, reintroducing bacteria, specifically from the Lactobacillus or Acetobacter genera, heightened the phenotypic severity in the bacteria-deprived mutants. These findings posit that particular native bacteria contribute to the severity of seizure-like phenotypes in paraShu. We further uncovered that treating paraShu with antibiotics boosted Nrf2 signaling in the gut, and that global Nrf2 activation mirrored the effects of removing bacteria from paraShu. This raises the possibility that the removal of commensal bacteria suppresses the seizure-like manifestations through augmented antioxidant responses. Since bacterial removal during development was critical for suppression of adult paraShu phenotypes, our research sets the stage for subsequent studies, aiming to elucidate the interplay between commensal bacteria and the developing nervous system in conditions predisposed to the hyperexcitable nervous system.
期刊介绍:
Genes, Brain and Behavior was launched in 2002 with the aim of publishing top quality research in behavioral and neural genetics in their broadest sense. The emphasis is on the analysis of the behavioral and neural phenotypes under consideration, the unifying theme being the genetic approach as a tool to increase our understanding of these phenotypes.
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