Glutamate Transport and Preterm Brain Injury

作者：Silvia Pregnolato, Ela Chakkarapani, Anthony R Isles, Karen Luyt · 发表于：Frontiers in Physiology · 年份：2019 · DOI：10.3389/fphys.2019.00417 · 被引用次数：71 · 研究领域：Neonatal and fetal brain pathology、Metabolism and Genetic Disorders、Neonatal Respiratory Health Research

Preterm birth complications are the leading cause of child death worldwide and a top global health priority. Among the survivors, the risk of life-long disabilities is high, including cerebral palsy and impairment of movement, cognition, and behavior. Understanding the molecular mechanisms of preterm brain injuries is at the core of future healthcare improvements. Glutamate excitotoxicity is a key mechanism in preterm brain injury, whereby the accumulation of extracellular glutamate damages the delicate immature oligodendrocytes and neurons, leading to the typical patterns of injury seen in the periventricular white matter. Glutamate excitotoxicity is thought to be induced by an interaction between environmental triggers of injury in the perinatal period, particularly cerebral hypoxia-ischemia and infection/inflammation, and developmental and genetic vulnerabilities. To avoid extracellular build-up of glutamate, the brain relies on rapid uptake by sodium-dependent glutamate transporters. Astrocytic excitatory amino acid transporter 2 (EAAT2) is responsible for up to 95% of glutamate clearance, and several lines of evidence suggest that it is essential for brain functioning. While in the adult EAAT2 is predominantly expressed by astrocytes, EAAT2 is transiently upregulated in the immature oligodendrocytes and selected neuronal populations during mid-late gestation, at the peak time for preterm brain injury. This developmental upregulation may interact with perinatal hypoxia-is...