Center for Child and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Institute of Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
Exp Neurol. 2020 Sep;331:113330. doi: 10.1016/j.expneurol.2020.113330. Epub 2020 Apr 25.
Chronic hyperammonemia is a common condition affecting individuals with inherited urea cycle disorders resulting in progressive cognitive impairment and behavioral abnormalities. Altered neurotransmission has been proposed as major source of neuronal dysfunction during chronic hyperammonemia, but the molecular pathomechanism has remained incompletely understood. Here we show that chronic exposure to ammonium acetate induces locomotor dysfunction and abnormal feeding behavior in zebrafish larvae, indicative for an impairment of higher brain functions. Biochemically, chronically elevated ammonium concentrations cause enhanced activity of glutamate decarboxylase isoforms GAD1 and GAD2 with increased formation of GABA and concomitant depletion of glutamate, ultimately leading to a dysfunctional hypoglutamatergic and hyperGABAergic metabolic state. Moreover, elevated GABA concentrations are accompanied by increased expression of GABA receptor subunits alpha-1, gamma-2 and delta, supporting the notion of an increased GABA tone in chronic hyperammonemia. Propionate oxidation as major anaplerotic reaction sufficiently compensates for the transamination-dependent withdrawal of 2-oxoglutarate, thereby preventing bioenergetic dysfunction under chronic hyperammonemic conditions. Thus, our study extends the hypothesis of alterations in the glutamatergic and GABAergic system being an important pathophysiological factor causing neurobehavioral impairment in chronic hyperammonemia. Given that zebrafish larvae have already been successfully used for high-throughput identification of novel compounds to treat inherited neurological diseases, the reported zebrafish model should be considered an important tool for systematic drug screening targeting altered glutamatergic and GABAergic metabolism under chronic hyperammonemic conditions in the future.
慢性高血氨症是一种常见病症，影响患有遗传性尿素循环障碍的个体，导致进行性认知障碍和行为异常。已提出神经递质改变是慢性高血氨症期间神经元功能障碍的主要来源，但分子发病机制仍不完全清楚。在这里，我们显示慢性暴露于乙酸铵会诱导斑马鱼幼虫的运动功能障碍和异常摄食行为，表明大脑高级功能受损。从生化角度来看，持续升高的铵浓度会导致谷氨酸脱羧酶同工酶 GAD1 和 GAD2 的活性增强，GABA 的形成增加，同时谷氨酸耗竭，最终导致谷氨酸能功能障碍和 GABA 能代谢状态异常。此外，升高的 GABA 浓度伴随着 GABA 受体亚基 alpha-1、gamma-2 和 delta 的表达增加，支持慢性高血氨症中 GABA 张力增加的观点。作为主要的氨同化反应，丙酸盐氧化充分补偿了转氨基作用引起的 2-酮戊二酸的消耗，从而防止了慢性高血氨条件下的生物能功能障碍。因此，我们的研究扩展了谷氨酸能和 GABA 能系统改变是导致慢性高血氨症神经行为损伤的重要病理生理因素的假说。鉴于斑马鱼幼虫已成功用于高通量鉴定治疗遗传性神经疾病的新型化合物，所报道的斑马鱼模型应被视为在未来针对慢性高血氨症下谷氨酸能和 GABA 能代谢改变进行系统药物筛选的重要工具。
