Chromatin Acetylation, Memory, and LTP Are Impaired in CBP+/− Mice

Alarcón, Juan Marcos; Malleret, Gaël; Touzani, Khalid; Vronskaya, Svetlana; Ishii, Shunsuke; Kandel, Eric R.; Barco, Ángel

doi:10.1016/j.neuron.2004.05.021

Cited by 818 publications

(349 citation statements)

References 45 publications

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“…We found evidence for regulation of histone acetylation by contextual fear conditioning in the hippocampus, suggesting that at least one form of epigenetic mark is regulated during formation of long term memory in mammals (23). Other studies have implicated the histone acetyltransferase CREB-binding protein in formation of hippocampus-dependent long term memory (25)(26)(27). Together, these studies suggest that epigenetic modulation of the genome is a necessary component to formation of long term memory.…”

supporting

confidence: 50%

“…Long term potentiation (LTP) of hippocampal Schaffer collateral synapses has received a great deal of experimental attention, since this form of synaptic plasticity utilizes many of the same mechanisms involved in consolidation of long term memory (35). Successful formation of LTP requires engagement of NMDA receptors, activation of the Ras-MEK-ERK signaling cascade, and ultimately posttranslational modifications of histones that mediate a transcriptional program resulting in lasting changes in neuronal function (23,(25)(26)(27)36). Because DNA methylation and histone post-translational modification are intimately associated, we speculated that DNMT activity might regulate synaptic plasticity mechanisms in the CNS.…”

mentioning

confidence: 99%

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Evidence That DNA (Cytosine-5) Methyltransferase Regulates Synaptic Plasticity in the Hippocampus

Levenson¹,

Roth²,

Lubin³

et al. 2006

Journal of Biological Chemistry

572

449

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DNA (cytosine-5) methylation represents one of the most widely used mechanisms of enduring cellular memory. Stable patterns of DNA methylation are established during development, resulting in creation of persisting cellular phenotypes. There is growing evidence that the nervous system has co-opted a number of cellular mechanisms used during development to subserve the formation of long term memory. In this study, we examined the role DNA (cytosine-5) methyltransferase (DNMT) activity might play in regulating the induction of synaptic plasticity. We found that the DNA within promoters for reelin and brain-derived neurotrophic factor, genes implicated in the induction of synaptic plasticity in the adult hippocampus, exhibited rapid and dramatic changes in cytosine methylation when DNMT activity was inhibited. Moreover, zebularine and 5-aza-2-deoxycytidine, inhibitors of DNMT activity, blocked the induction of long term potentiation at Schaffer collateral synapses. Activation of protein kinase C in the hippocampus decreased reelin promoter methylation and increased DNMT3A gene expression. Interestingly, DNMT activity is required for protein kinase C-induced increases in histone H3 acetylation. Considered together, these results suggest that DNMT activity is dynamically regulated in the adult nervous system and that DNMT may play a role in regulating the induction of synaptic plasticity in the mature CNS. DNA (cytosine-5) methyltransferases (DNMTs)5 are a family of enzymes that catalyze the methylation of cytosine residues (1-5). Many biological processes, including imprinting, differentiation, X-chromosome inactivation, and long term transcriptional regulation, involve cytosine methylation, a covalent modification of DNA (6, 7). Tissue-specific patterns of DNA methylation are established early during development as a consequence of cellular differentiation (8, 9). Expression and activity of DNMT is generally restricted to dividing cells and is very high during early development (5, 10 -13). In most cell types, DNMT expression diminishes greatly once terminal differentiation occurs (5, 10 -14).The mammalian brain consists primarily of postmitotic neurons and glial cells that possess relatively low proliferative potential. In addition, there are small populations of stem cells in various regions of the brain that have the potential to develop into new neurons (15). Therefore, reports that the adult central nervous system (CNS) possesses relatively high levels of DNMT mRNA and enzyme activity were surprising (5, 13, 16). Early studies into the function of DNMT in the brain suggested that this enzyme might be involved in DNA repair and neurodegeneration (16 -19). Important recent studies also have implicated misregulation of DNMT specifically or DNA methylation in general in such cognitive disorders as schizophrenia, Rett syndrome, and Fragile X mental retardation (20 -22).Epigenetics refers to a set of self-perpetuating post-translational modifications of DNA and nuclear proteins that produce lasting alterations in ch...

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supporting

confidence: 50%

mentioning

confidence: 99%

Evidence That DNA (Cytosine-5) Methyltransferase Regulates Synaptic Plasticity in the Hippocampus

Levenson¹,

Roth²,

Lubin³

et al. 2006

Journal of Biological Chemistry

572

449

View full text Add to dashboard Cite

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“…Neuroscientists had assumed that the cognitive defects caused by the syndrome were irreversible -especially as the condition can be diagnosed before birth. But in 2003, Tully and several others showed that administering drugs that increase CREB activity in mouse models of the disease dramatically improves the animals' ability to learn [4][5][6] . "We get complete recovery in adult mice, " says Mark Mayford, a neuroscientist at the Scripps Research Institute in La Jolla, Califor nia, who was an author on one of the studies.…”

Section: The Damage Undonementioning

confidence: 99%

Neuroscience: Small, furry … and smart

Lehrer¹

2009

Nature

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“…Activated CREB affects acetylation of specific target genes by recruitment of CBP, a HAT that is mutated in Rubinstein Taybi syndrome, an ID disorder (36). In mice, heterozygous mutations in CBP cause LTM defects in an object recognition assay (41,42), which were rescued by pharmacological activation of CREB (43). The requirement of CBP in object recognition LTM is dependent on its ability to bind to CREB and on its HAT activity (44,45), suggesting that CBP regulates LTM by acetylating histones at CREB target genes.…”

Section: Histone Acetylationmentioning

confidence: 99%

“…In a mouse model for age dependent cognitive decline, aged mice with cognitive defects did not exhibit the normal pattern of increased histone acetylation and altered gene expression in response to fear conditioning, and these age-dependent molecular defects were also rescued by HDACi treatment (57). Furthermore, HDACi treatment has been shown to rescue LTM and LTP defects in many other rodent models for neurodegenerative disease, age dependent cognitive decline, and ID (41,55,(58)(59)(60)(61). Taken together, these studies suggest that modulation of chromatin structure through histone acetylation is an important process in learning and memory and may be relevant to cognitive disorders, such as ID, neurodegenerative disease, and age dependent cognitive decline.…”

Section: Histone Acetylationmentioning

confidence: 99%

Epigenetic regulation of memory: implications in human cognitive disorders

Kramer

2013

BioMolecular Concepts

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Epigenetic modification of chromatin structure is an important mechanism in the regulation of gene expression. Recent studies have shown that dynamic regulation of chromatin structure occurs in response to neuronal stimulation associated with learning and memory. Learning-induced chromatin modifications include DNA methylation, histone acetylation, histone phosphorylation and histone methylation. Studies in animal models have used genetic and pharmacological methods to manipulate the epigenetic machinery in the brain during learning and memory formation. In general, these studies suggest that epigenetic regulation of chromatin structure is essential for long term memory (LTM) consolidation, which is known to require new gene transcription. Analysis of animal models has also implicated epigenetic mechanisms in impaired cognition associated with aging, neurodegenerative disease, and intellectual disability (ID). Recently, it has been shown that a subset of ID disorders and autism are caused by disruption of specific chromatin modification complexes that are involved in nuclear hormone receptor mediated transcriptional regulation. This review provides an overview of chromatin modifications that are implicated in learning and memory and discusses the role of chromatin modifying proteins in learning-induced transcriptional regulation and human cognitive disorders.

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Chromatin Acetylation, Memory, and LTP Are Impaired in CBP+/− Mice

Cited by 818 publications

References 45 publications

Evidence That DNA (Cytosine-5) Methyltransferase Regulates Synaptic Plasticity in the Hippocampus

Evidence That DNA (Cytosine-5) Methyltransferase Regulates Synaptic Plasticity in the Hippocampus

Neuroscience: Small, furry … and smart

Epigenetic regulation of memory: implications in human cognitive disorders

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