Endogenous formaldehyde is a memory-related molecule in mice and humans
Endogenous formaldehyde is a memory-related molecule in mice and humans
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DOI：
10.1038/s42003-019-0694-x
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发表时间：
2019-11-29
影响因子：
5.9
通讯作者：
Tong, Zhiqian
中科院分区：
文献类型：
--
作者：
Ai, Li;Tan, Tao;Tong, Zhiqian
气态甲醛是地球演化早期形成的一种有机小分子。尽管甲醛在高浓度下有毒，但它在细胞新陈代谢中发挥着重要作用，甚至在健康的大脑中也发现了甲醛。然而，它在大脑中的病理生理功能尚不清楚。在这里，我们报告了在生理条件下，空间学习活动导致线粒体肌氨酸脱氢酶(SARDH)快速产生甲醛。我们发现，高水平的甲醛通过增强N-甲基-D-天冬氨酸(NMDA)电流来促进空间记忆的形成，但高浓度的甲醛通过C232残基将NR1亚单位与NR2B交联，从而逐渐失活NMDA受体。我们还报告了在乙醛脱氢酶-2(ALDH2)基因敲除的小鼠中，由于ALDH2功能低下而导致的甲醛积累损害了记忆，这与阿尔茨海默病患者的观察结果一致。我们还发现，在患有肌氨酸血症的儿童或SADH缺失的小鼠中，由于线粒体SARDH基因突变而导致的甲醛缺乏会导致认知障碍。因此，我们得出结论，内源性甲醛通过NMDA受体调节学习和记忆。
Gaseous formaldehyde is an organic small molecule formed in the early stages of earth's evolution. Although toxic in high concentrations, formaldehyde plays an important role in cellular metabolism and, unexpectedly, is found even in the healthy brain. However, its pathophysiological functions in the brain are unknown. Here, we report that under physiological conditions, spatial learning activity elicits rapid formaldehyde generation from mitochondrial sarcosine dehydrogenase (SARDH). We find that elevated formaldehyde levels facilitate spatial memory formation by enhancing N-methyl-D-aspartate (NMDA) currents, but that high formaldehyde concentrations gradually inactivate the NMDA receptor by cross-linking NR1 subunits to NR2B via the C232 residue. We also report that in mice with aldehyde dehydrogenase-2 (ALDH2) knockout, formaldehyde accumulation due to hypofunctional ALDH2 impairs memory, consistent with observations of Alzheimer's disease patients. We also find that formaldehyde deficiency caused by mutation of the mitochondrial SARDH gene in children with sarcosinemia or in mice with Sardh deletion leads to cognitive deficits. Hence, we conclude that endogenous formaldehyde regulates learning and memory via the NMDA receptor.