Endogenous formaldehyde is a memory-related molecule in mice and humans

Li Ai,Xuechao Fei,Rui Wang,Xiaoming Wang,Hongbin Han,Xu Yang,Shangying Bai,Weishan Wang,Shengjie Zhao,Tao Tan,Weiying Lin,Zhiqian Tong,Dehua Cui,Yalan Di,Yan Yu,Yonghe Tang,Jun Yang,Aibo Wang,Rong He ,Xiang Cai

doi:10.1038/s42003-019-0694-x

Abstract

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 via the C232 residue of the NMDA receptor, but that high formaldehyde concentrations gradually inactivate the receptor by cross-linking NR1 subunits to NR2B. We also report that in mice with aldehyde dehydrogenase-2 (ALDH2) knockout, formaldehyde accumulation due to hypofunctional ALDH2 impairs memory, consistent with observations of Alzheimerʼs 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.

Highlights

Sarcosinemia is a rare pediatric neurodegenerative disease characterized by high levels of sarcosine in the blood and urine[16], mental retardation, speech disorder, and ataxia[17]
To investigate the role of brain formaldehyde in cognitive processes, we examined whether hippocampal formaldehyde concentration changes after spatial learning activity in Morris water maze (MWM) in the wild-type adult male Sprague−Dawley (SD) rats
We observed that healthy rats exhibited a rapid reduction in escape latency during training and significantly greater time spent in the target quadrant compared to nontarget quadrants during the probe test (Fig. 1a, b), suggesting that a classical spatial memory was forming in these rats

Summary

Introduction

Sarcosinemia is a rare pediatric neurodegenerative disease characterized by high levels of sarcosine in the blood and urine[16], mental retardation (low intelligence quotient, intelligence quotient), speech disorder, and ataxia[17]. It is a recessive inherited disease linked to loss-of-function mutations in the sarcosine dehydrogenase gene (SARDH), resulting in ~4-fold reduced SARDH activity in the mitochondria. SARDH produces free formaldehyde in the conversion of sarcosine to glycine[18], raising the possibility that the cognitive deficits of sarcosinemia are associated with brain formaldehyde deficiency. Our findings suggest that endogenous formaldehyde bidirectionally modulates cognition via NMDA-R, with both insufficiency and overabundance resulting in cognitive deficits

Methods

Results

Conclusion