Interdisciplinary Graduate Program in Genetics, Graduate College, University of Iowa, Iowa City, Iowa, USA.
Department of Anesthesia, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
Genes Brain Behav. 2024 Oct;23(5):e70000. doi: 10.1111/gbb.70000.
Mutations in voltage-gated sodium (Na) channels, which are essential for generating and propagating action potentials, can lead to serious neurological disorders, such as epilepsy. However, disease-causing Na 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 para-a gain-of-function mutant of the Drosophila Na channel gene, paralytic. Remarkably, the elimination of endogenous bacteria considerably ameliorated neurological impairments in para. 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 para. We further uncovered that treating para with antibiotics boosted Nrf2 signaling in the gut, and that global Nrf2 activation mirrored the effects of removing bacteria from para. 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 para 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.
电压门控钠 (Na) 通道的突变是产生和传播动作电位的关键，可导致严重的神经紊乱，如癫痫。然而，致病的 Na 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的显著影响，这些因素统称为“暴露组”。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。尽管这些细菌在正常情况下通常对神经系统有益，但它们在病理状态下的影响在很大程度上仍然未知。在这里，我们研究了共生微生物对果蝇 Na 通道基因 paralytic 的功能获得性突变体 para 表现出的癫痫样表型的影响。值得注意的是，内源性细菌的消除显著改善了 para 的神经损伤。一致地，重新引入细菌，特别是来自乳酸杆菌或醋杆菌属的细菌，加剧了在缺乏细菌的突变体中的表型严重程度。这些发现表明特定的本土细菌有助于 para 中癫痫样表型的严重程度。我们进一步发现，用抗生素治疗 para 会增强肠道中的 Nrf2 信号，而全局 Nrf2 激活反映了从 para 中去除细菌的效果。这提出了这样一种可能性，即共生细菌的去除通过增强抗氧化反应来抑制癫痫样表现。由于在发育过程中去除细菌对于抑制成年 para 表型至关重要，我们的研究为随后的研究奠定了基础，旨在阐明共生细菌与易发生神经兴奋的神经系统发育中的神经系统之间的相互作用。
