Laboratory of Regulation of Brain Neuron Functions, Pavlov Institute of Physiology, Russian Academy of Sciences, Makarova emb. 6, Saint-Petersburg, Russia, 199034.
Department of Biochemistry, Faculty of Biology, Saint-Petersburg State University, Universitetskaya emb. 7-9, Saint-Petersburg, Russia, 199034.
Neurochem Res. 2021 Mar;46(3):550-563. doi: 10.1007/s11064-020-03191-z. Epub 2021 Jan 2.
Prenatal hypoxia is among leading causes of progressive brain pathologies in postnatal life. This study aimed to analyze the characteristics of the hippocampal glutamatergic system and behavior of rats in early (2 weeks), adult (3 months) and advanced (18 months) postnatal ontogenesis after exposure to prenatal severe hypoxia (PSH, 180 Torr, 5% O2, 3 h) during the critical period in the formation of the hippocampus (days 14-16 of gestation). We have shown an age-dependent progressive decrease in the hippocampal glutamate levels, a decrease of the neuronal cell number in the CA1 hippocampal region, as well as impairment of spatial long-term memory in the Morris water navigation task. The gradual decrease of glutamate was accompanied by decreased expression of the genes that mediate glutamate metabolism and recycling in the hippocampus. That deficiency apparently correlated with an increase of the metabotropic glutamate receptor type 1 (mGluR1) and synaptophysin expression. Generation of the lipid peroxidation products in the hippocampus of adult rats subjected to prenatal severe hypoxia (PSH rats) was not increased compared to the control animals when tested in a model of glutamate excitotoxicity induced by severe hypoxia. This demonstrates that excessive glutamate sensitivity in PSH rats does not compensate for glutamate deficiency. Our results show a significant contribution of the glutamate system dysfunction to age-associated decrease of this mediator, cognitive decline, and early neuronal loss in PSH rats.
产前缺氧是产后进行性脑病理学的主要原因之一。本研究旨在分析经历围生期严重缺氧（PSH，180 托，5%O2，3 小时）后，在海马形成的关键时期（妊娠第 14-16 天），大鼠在早期（2 周）、成年（3 个月）和晚期（18 个月）出生后发育过程中，海马谷氨酸能系统的特征和行为。我们已经显示出海马谷氨酸水平随年龄呈进行性下降，CA1 海马区神经元细胞数量减少，以及在 Morris 水迷宫任务中空间长期记忆受损。谷氨酸的逐渐减少伴随着介导海马体中谷氨酸代谢和再循环的基因表达降低。这种缺陷显然与代谢型谷氨酸受体 1（mGluR1）和突触小体蛋白表达的增加有关。与对照动物相比，在由严重缺氧诱导的谷氨酸兴奋性毒性模型中，接受产前严重缺氧的成年大鼠（PSH 大鼠）海马体中的脂质过氧化产物生成并未增加，这表明 PSH 大鼠中过度的谷氨酸敏感性不能弥补谷氨酸的缺乏。我们的研究结果表明，谷氨酸系统功能障碍对年龄相关的这种介质的减少、认知能力下降和 PSH 大鼠的早期神经元丢失有显著贡献。
