Huff Alyssa, Oliveira Luiz Marcelo, Karlen-Amarante Marlusa, Ebiala Favour, Ramirez Jan Marino, Kalume Franck
Norecliffe Foundation Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, United States of America.
Norecliffe Foundation Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, United States of America; Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA 98108, USA.
Exp Neurol. 2025 Mar;385:115123. doi: 10.1016/j.expneurol.2024.115123. Epub 2024 Dec 20.
Swallowing, both nutritive and non-nutritive, is highly dysfunctional in children with Leigh Syndrome (LS) and contributes to the need for both gastrostomy and tracheostomy tube placement. Without these interventions aspiration of food, liquid, and mucus occur resulting in repeated bouts of respiratory infection. No study has investigated whether mouse models of LS, a neurometabolic disorder, exhibit dysfunctions in neuromuscular activity of swallow and breathing integration. We used a genetic mouse model of LS in which the NDUFS4 gene is knocked out (KO) specifically in Vglut2 or Gad2 neurons. We found increased variability of the swallow motor pattern, disruption in breathing regeneration post swallow, and water-induced apneas only in Vglut2 KO mice. These physiological changes likely contribute to weight loss and premature death seen in this mouse model. Following chronic hypoxia (CH) exposure, there was no difference in swallow motor pattern, breathing regeneration, weight, and life expectancy in the Vglut2-Ndufs4-KO CH mice compared to control CH, indicating a phenotypic rescue or prevention. These findings show that like patients with LS, Ndufs4 mouse models of LS exhibit swallow impairments as well as swallow-breathing discoordination alongside the other phenotypic traits described in previous studies. Understanding this aspect of LS will open roads for the development of future more efficacious therapeutic intervention for this illness.
无论是营养性吞咽还是非营养性吞咽，在患有 Leigh 综合征（LS）的儿童中都存在高度功能障碍，这使得胃造口术和气管造口术置管成为必要。如果没有这些干预措施，食物、液体和黏液的误吸就会发生，导致反复的呼吸道感染。尚无研究调查 LS（一种神经代谢紊乱疾病）的小鼠模型在吞咽和呼吸整合的神经肌肉活动中是否存在功能障碍。我们使用了一种 LS 的基因小鼠模型，其中 NDUFS4 基因在 Vglut2 或 Gad2 神经元中被特异性敲除（KO）。我们发现，仅在 Vglut2 KO 小鼠中，吞咽运动模式的变异性增加、吞咽后呼吸恢复中断以及水诱导的呼吸暂停。这些生理变化可能导致该小鼠模型出现体重减轻和过早死亡。在慢性缺氧（CH）暴露后，与对照 CH 组相比，Vglut2-Ndufs4-KO CH 小鼠的吞咽运动模式、呼吸恢复、体重和预期寿命没有差异，表明存在表型挽救或预防。这些发现表明，与 LS 患者一样，LS 的 Ndufs4 小鼠模型除了先前研究中描述的其他表型特征外，还表现出吞咽障碍以及吞咽 - 呼吸失调。了解 LS 的这一方面将为未来开发更有效的该疾病治疗干预措施开辟道路。
