Increase in hippocampal histone H3K9me3 is negatively correlated with memory in old male mice

Kushwaha, Akanksha; Thakur, M. K.

doi:10.1007/s10522-019-09850-1

Cited by 24 publications

(19 citation statements)

References 64 publications

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“…Mechanistically, our finding supports the notion that newborn neurons contribute greatly to the pattern separation of memories and epigenetic modifiers could be beneficial in treating those diseases via modulating the expression of synaptic proteins in hippocampus. SUV39H1 is one of the most essential methyltransferases that play a critical role in the formation and regulation of memory (Ding et al, 2017; Kushwaha & Thakur, 2020; Snigdha et al, 2016). Here we further demonstrated that Suv39h1 regulates synaptic gene expression in an activity‐dependent manner in the newly matured newborn neurons and provided mechanical insights into the epigenetic regulation in a timely precision manner in memory processing.…”

Section: Discussionmentioning

confidence: 99%

Suv39h1 regulates memory stability by inhibiting the expression of Shank1 in hippocampal newborn neurons

Chen

Ding

Guo

et al. 2022

Eur J of Neuroscience

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Adult newborn neurons are involved in memory encoding and extinction, but the neural mechanism is unclear. We found the adult newborn neurons at 4 weeks are recruited by learning and subjected to epigenetic regulations, consequently reducing their ability to be re‐recruited later. After removal of the epigenetic blockage, Suv39h1 KO mice showed an increased recruiting number of aged newborn neurons and enhanced flexibility in learning tasks. Besides NRXN1, we found SHANK1, the synaptic scaffold protein, is one of the major targets of Suv39h1, regulating memory stability. Expression of Shank1 is transiently engaged to enhance synaptogenesis during learning and is strongly suppressed by Suv39h1 from 5 h after learning. Exogenously overexpression of Shank1 in dentate gyrus increased the density of mushroom spines and decreased the persistency of old memories. Our study indicated the activity‐regulated epigenetic modification in newly matured newborn neurons in hippocampus insulates temporally distinct experiences and stabilizes old memories.

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Section: Discussionmentioning

confidence: 99%

Suv39h1 regulates memory stability by inhibiting the expression of Shank1 in hippocampal newborn neurons

Chen

Ding

Guo

et al. 2022

Eur J of Neuroscience

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“…The increased sensitivity of 21 DIV cultures also made them more challenging to produce than less stressed 6 and 12 DIV neurons. A recent study found that although hippocampal H3K9me3 was elevated in both adult and aged mice, the greatest elevation was in adult mice ( Kushwaha and Thakur, 2020 ). This is consistent with our prior research since we did not examine the adult mouse population and found that H3K9me3 was elevated in aged mice in comparison to young mice ( Snigdha et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibiting BDNF Signaling Upregulates Hippocampal H3K9me3 in a Manner Dependent On In Vitro Aging and Oxidative Stress

et al. 2022

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Histone modifications are key contributors to the cognitive decline that occurs in aging and Alzheimer’s disease. Our lab has previously shown that elevated H3K9me3 in aged mice is correlated with synaptic loss, cognitive impairment and a reduction in brain derived neurotrophic factor (BDNF). However, the mechanism of H3K9me3 regulation remains poorly understood. In this study, we investigated the role of age-associated stressors on H3K9me3 regulation and examined if changes in H3K9me3 were age dependent. We used cultured hippocampal neurons at 6, 12, and 21 days in vitro (DIV) to examine the effect of different stressors on H3K9me3 across neuron ages. We found that the oxidative stressor hydrogen peroxide (H2O2) does not induce H3K9me3 in 12 DIV neurons. Inhibiting BDNF signaling via TrkB-Fc elevated H3K9me3 in 12 and 21 DIV neurons compared to 6 DIV neurons. Antioxidant treatment prevented H3K9me3 elevation in 12 DIV neurons treated with TrkB-Fc and H2O2. H2O2 elevated the epigenetic regulator SIRT1 in 6 DIV neurons but did not increase H3K9me3 levels. Our findings demonstrate that inhibiting BDNF signaling elevates hippocampal H3K9me3 in a manner dependent on in vitro age and oxidative stress.

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“…Methylation of histones H3 typically occurring at specific lysine (K) residues, such as H3K9, H3K27 regulates chromatin state and plays an important role in the regulation of gene expression. In particular, trimethylation of H3K9 (H3K9me3) and H3K27 (H3K27me3) which regulates silent heterochromatin stability has been implicated in agedependent cognitive impairment [7,8]. We AGING hypothesized that rejuvenating effects of D+Q would affect the histone H3 methylation profile.…”

Section: Beneficial Effects Of D+q On Cognitive Skills In Aged Rats A...mentioning

confidence: 99%

“…In particular, methylation of histone H3 has been implicated in age-associated cognitive decline in mice. Aging causes upregulation of H3 trimethylation at lysine 3 (H3K9me3) [7] and downregulation at lysine 27 (H3K27me3) [8] in the mouse hippocampus. Recently it has been shown that the decrease in the H3K9me3 by systemic administration of an inhibitor of the principal enzyme responsible for the trimethylation of H3K9 (histone methyltransferase SUV39H1) improved memory performance in aged, but not young mice [9].…”

Section: Introductionmentioning

confidence: 99%

Combination of dasatinib and quercetin improves cognitive abilities in aged male Wistar rats, alleviates inflammation and changes hippocampal synaptic plasticity and histone H3 methylation profile

Krzystyniak

Wesierska

Petrazzo

et al. 2022

Aging

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Aging is associated with cognitive decline and accumulation of senescent cells in various tissues and organs. Senolytic agents such as dasatinib and quercetin (D+Q) in combination have been shown to target senescent cells and ameliorate symptoms of aging-related disorders in mouse models. However, the mechanisms by which senolytics improve cognitive impairments have not been fully elucidated particularly in species other than mice. To study the effect of senolytics on aging-related multifactorial cognitive dysfunctions we tested the spatial memory of male Wistar rats in an active allothetic place avoidance task. Here we report that 8 weeks treatment with D+Q alleviated learning deficits and memory impairment observed in aged animals. Furthermore, treatment with D+Q resulted in a reduction of the peripheral inflammation measured by the levels of serum inflammatory mediators (including members of senescent cell secretome) in aged rats. Significant improvements in cognitive abilities observed in aged rats upon treatment with D+Q were associated with changes in the dendritic spine morphology of the apical dendritic tree from the hippocampal CA1 neurons and changes in the level of histone H3 trimethylation at lysine 9 and 27 in the hippocampus. The beneficial effects of D+Q on learning and memory in aged rats were long-lasting and persisted at least 5 weeks after the cessation of the drugs administration. Our results expand and provide new insights to the existing knowledge associated with effects of senolytics on alleviating age-related associated cognitive dysfunctions.

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Increase in hippocampal histone H3K9me3 is negatively correlated with memory in old male mice

Cited by 24 publications

References 64 publications

Suv39h1 regulates memory stability by inhibiting the expression of Shank1 in hippocampal newborn neurons

Suv39h1 regulates memory stability by inhibiting the expression of Shank1 in hippocampal newborn neurons

Inhibiting BDNF Signaling Upregulates Hippocampal H3K9me3 in a Manner Dependent On In Vitro Aging and Oxidative Stress

Combination of dasatinib and quercetin improves cognitive abilities in aged male Wistar rats, alleviates inflammation and changes hippocampal synaptic plasticity and histone H3 methylation profile

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