Memory and synaptic plasticity are impaired by dysregulated hippocampal O-GlcNAcylation

Yang, Yong Ryoul; Song, Seungju; Hwang, Hongsik; Jung, Jung Hoon; Kim, Su-Jeong; Yoon, Susan A.; Hur, Jin‐Hoe; Park, Jae-Il; Lee, Cheol; Nam, Dougu; Seo, Young Kyo; Kim, Joung-Hun; Rhim, Hyewhon; Suh, Pann‐Ghill

doi:10.1038/srep44921

Cited by 31 publications

(50 citation statements)

References 53 publications

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“…A previous study compared the effects of in five different groups: naïve, electroshock sleep-deprived and yoked-control, fish exposed to constant light (increasing wakefulness), and fish exposed to constant darkness (increasing sleep). 26 In addition, older mice with decreased memory function demonstrate chronically increased O-GlcNAcylation relative to young mice and elevated O-GlcNAcylation is suggested to contribute to L/M impairment. It has been reported that total SD for 72 consecutive hours interferes with learning performance in a spatial associative learning task in zebrafish.…”

Section: Discussionmentioning

confidence: 99%

Sleep deprivation impairs learning and memory by decreasing protein O ‐GlcNAcylation in the brain of adult zebrafish

et al. 2019

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Sleep is an evolutionarily conserved physiological process implicated in the consolidation of learning and memory (L/M). Here, we report that sleep deprivation (SD)‐induced cognitive deficits in zebrafish are mediated through reduction in O‐GlcNAcylation of brain. Microarray‐based gene expression profiling of zebrafish brain demonstrated significant changes in genes involved in metabolism by SD or fear conditioning (FC), compared to the control group. In particular, it was observed that a marked decrease in the number of genes involved in carboxylic acid and organic acid metabolic processes in the brains of SD group compared to control group. SD downregulated O‐GlcNAc transferase (OGT) and O‐GlcNAcylation, while the expression of O‐GlcNAcase was upregulated. FC activated protein kinase A (PKA) and phosphorylated cAMP response element binding protein (p‐CREB), an effect that was greatly inhibited by SD. Moreover, FC upregulated expressions of OGT and increased O‐GlcNAcylation in the brains of normal but not SD zebrafish. Intriguingly, upregulation of O‐GlcNAcylation by glucosamine restored defects in L/M functions and PKA/p‐CREB activity in SD group. Our findings highlight the O‐GlcNAcylation changes in the brain during the L/M process and further provide a foundation for future studies seeking the molecular and biochemical mechanisms by which HBP of glucose metabolism affects cognitive function.

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Section: Discussionmentioning

confidence: 99%

Sleep deprivation impairs learning and memory by decreasing protein O ‐GlcNAcylation in the brain of adult zebrafish

et al. 2019

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“…In contrast to a decrease in sIPSC and mIPSC frequency in PrL layer II/III neurons, our group previously reported that mIPSC frequency remains unchanged in hippocampal CA1 neurons in Oga +/− mice 31 , indicating that the PrL layer II/III neurons are more sensitive to a decrease in OGA expression levels. This difference may result from the fact that the hippocampus is enriched with particularly high levels of OGT and OGA transcripts 44 , which may help to cope with the OGA heterozygosity.…”

Section: Discussionmentioning

confidence: 59%

“…Previous studies demonstrated that both spatial learning and hippocampal synaptic plasticity are impaired in Oga +/− mice 31,32 , and that a deficit in O-GlcNAc cycling is associated with neurodegenerative and metabolic diseases 37,38 . The immediate donor molecule for O-GlcNAcylation, UDP-GlcNAc, is produced from glucose via the HBP, and thus, the degree of O-GlcNAc modification changes rapidly depending on blood glucose levels.…”

Section: Discussionmentioning

confidence: 99%

“…Both OGT and OGA are highly expressed in the brain, and particularly enriched in the cortex and hippocampus 29 . Interestingly, abnormal O-GlcNAcylation levels are closely associated with deficits in brain functions, such as synaptic plasticity and intracellular signaling [30][31][32] .…”

mentioning

confidence: 99%

“…Recently, two research groups, including our own laboratory, have independently reported that O-GlcNAc modification in the hippocampus plays an important role in regulating neuronal excitability as well as cognitive functions [31][32][33][34] . In addition, impaired O-GlcNAc cycling is also implicated in pathological conditions, such as diabetes and Alzheimer diseases 26,35 .…”

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confidence: 99%

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Elevated O-GlcNAcylation induces an antidepressant-like phenotype and decreased inhibitory transmission in medial prefrontal cortex

Cho

Hwang

Rahman

et al. 2020

Sci Rep

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Depression is a devastating mental disorder affected by multiple factors that can have genetic, environmental, or metabolic causes. Although previous studies have reported an association of dysregulated glucose metabolism with depression, its underlying mechanism remains elusive at the molecular level. A small percentage of glucose is converted into uridine diphosphate-Nacetylglucosamine (UDP-GlcNAc) via the hexosamine biosynthetic pathway, which serves as an immediate donor for protein O-GlcNAc modification. O-GlcNAcylation is a particularly common posttranslational modification (PTM) in the brain, and the functional significance of O-GlcNAcylation in neurodegenerative diseases has been extensively reported. However, whether the degree of O-GlcNAc modification is associated with depressive disorder has not been examined. In this study, we show that increased o-GlcnAcylation levels reduce inhibitory synaptic transmission in the medial prefrontal cortex (mPFC), and that Oga +/− mice with chronically elevated o-GlcnAcylation levels exhibit an antidepressant-like phenotype. Moreover, we found that virus-mediated expression of OGA in the mPFC restored both antidepressant-like behavior and inhibitory synaptic transmission. Therefore, our results suggest that O-GlcNAc modification in the mPFC plays a significant role in regulating antidepressant-like behavior, highlighting that the modulation of O-GlcNAcylation levels in the brain may serve as a novel therapeutic candidate for antidepressants. Depressive disorder is a devastating mental disorder characterized by symptoms such as loss of interest, low mood, fatigue, and diminished cognitive functions 1-3. A deficit in monoamine metabolism including serotonin, dopamine, and norepinephrine is known to contribute to its etiology 4-6 , and the regulation of synaptic function through monoamine neurotransmitters serves as the primary approach to treat patients with depressive disorder 7,8. In addition, malfunctions of neuronal networks, such as an impaired balance between excitatory and inhibitory inputs, modulate emotional states, and previous studies suggest that glutamatergic and GABAergic systems are impaired in patients with depression 2,9,10. Furthermore, altered GABAergic inhibitory function induced by a change in the expression levels of GABAergic receptors also disrupts emotional processes in animal models of depressive disorders 9-14. Although the monoamine theory plays a major role in understanding the pathogenesis of depression, how the monoamine-independent changes in molecular and synaptic functions of neural networks contribute to depressive disorders remains largely elusive. The medial prefrontal cortex (mPFC) underlies the executive control of animal behavior 15,16 , and structural and functional changes in the mPFC, such as synaptic transmission and altered protein expression levels, are implicated in depression-related behaviors in animal models 15-18. For example, the deletion of the N-methyl-D-aspartic

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The emerging link between O-GlcNAcylation and neurological disorders

et al. 2017

Cell. Mol. Life Sci.

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O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is involved in the regulation of many cellular cascades and neurological diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and stroke. In the brain, the expression of O-GlcNAcylation is notably heightened, as is that of O-linked N-acetylglucosaminyltransferase (OGT) and β-N-acetylglucosaminidase (OGA), the presence of which is prominent in many regions of neurological importance. Most importantly, O-GlcNAcylation is believed to contribute to the normal functioning of neurons; conversely, its dysregulation participates in the pathogenesis of neurological disorders. In neurodegenerative diseases, O-GlcNAcylation of the brain's key proteins, such as tau and amyloid-β, interacts with their phosphorylation, thereby triggering the formation of neurofibrillary tangles and amyloid plaques. An increase of O-GlcNAcylation by pharmacological intervention prevents neuronal loss. Additionally, O-GlcNAcylation is stress sensitive, and its elevation is cytoprotective. Increased O-GlcNAcylation ameliorated brain damage in victims of both trauma-hemorrhage and stroke. In this review, we summarize the current understanding of O-GlcNAcylation's physiological and pathological roles in the nervous system and provide a foundation for development of a therapeutic strategy for neurological disorders.

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Memory and synaptic plasticity are impaired by dysregulated hippocampal O-GlcNAcylation

Cited by 31 publications

References 53 publications

Sleep deprivation impairs learning and memory by decreasing protein O ‐GlcNAcylation in the brain of adult zebrafish

Sleep deprivation impairs learning and memory by decreasing protein O ‐GlcNAcylation in the brain of adult zebrafish

Elevated O-GlcNAcylation induces an antidepressant-like phenotype and decreased inhibitory transmission in medial prefrontal cortex

The emerging link between O-GlcNAcylation and neurological disorders

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