REM sleep deprivation impairs learning and memory by decreasing brain O-GlcNAc cycling in mouse

다국어 초록 (Multilingual Abstract)

Rapid eye movement (REM) sleep is associated with learning and memory (L/M) functions. Here, we demonstrate that REM sleep deprivation (REMSD)-induced impairment of contextual fear memory and spatial memory in mouse is linked to a downregulation in hexosamine biosynthetic pathway (HBP)/O-GlcNAc flux in mouse brain. In mice exposed to REMSD, O-GlcNAcylation proteins and O-GlcNAc transferase (OGT) were decreased while O-GlcNAcase was increased compared to control mouse brain. Foot shock fear conditioning (FC) induced activation of protein kinase A (PKA) and cAMP response element binding protein (CREB), which were significantly inhibited in brains of the REMSD group. Intriguingly, increasing O-GlcNAc cycling with glucosamine (GlcN) or OGA inhibitor, Thiamet G, restored defects in L/M functions and FC-induced PKA/CREB activation induced by REMSD. On behavior test, GlcN restored the contextual fear memory and spatial memory impairment induced by REMSD. Furthermore, Thiamet G restored the REMSD-induced decrease in dendritic spine density and learning and memory impairment. Suppression of O-GlcNAcylation by the glutamine fructose-6-phosphate amidotransferase (GFAT) inhibitor, 6‐diazo‐5‐oxo‐l‐norleucine (DON), or OGT inhibitor, OSMI-1, impaired memory function and inhibited FC-induced PKA/CREB activation. To our knowledge, this is the first study to provide comprehensive evidence of dynamic O-GlcNAcylation changes during the L/M process in mice and defects in this pathway in the brain of REM sleep-deprived mice. Our collective results highlight HBP/O-GlcNAc cycling as a novel molecular link between sleep and cognitive function.