Epigenetic codes in cognition and behaviour.
TL;DR: Recent findings on the role and mechanisms of epigenetic codes in the brain are described, and their implication in synaptic plasticity, cognitive functions and psychiatric disorders are discussed.
About: This article is published in Behavioural Brain Research.The article was published on 2008-09-01. It has received 260 citations till now. The article focuses on the topics: Epigenetic code & Epigenetics.
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TL;DR: These studies indicate that SES is an important predictor of neurocognitive performance, particularly of language and executive function, and that S ES differences are found in neural processing even when performance levels are equal.
1,258 citations
TL;DR: An epigenetic molecular mechanism potentially underlying lifelong and transgenerational perpetuation of changes in gene expression and behavior incited by early abuse and neglect is highlighted.
1,176 citations
TL;DR: The results of this work suggest that patterns of transcription regulation represent the molecular signatures of long-term synaptic changes and memory formation.
Abstract: Transcription is a molecular requisite for long-term synaptic plasticity and long-term memory formation. Thus, in the last several years, one main interest of molecular neuroscience has been the identification of families of transcription factors that are involved in both of these processes. Transcription is a highly regulated process that involves the combined interaction and function of chromatin and many other proteins, some of which are essential for the basal process of transcription, while others control the selective activation or repression of specific genes. These regulated interactions ultimately allow a sophisticated response to multiple environmental conditions, as well as control of spatial and temporal differences in gene expression. Evidence based on correlative changes in expression, genetic mutations, and targeted molecular inhibition of gene expression have shed light on the function of transcription in both synaptic plasticity and memory formation. This review provides a brief overview ...
902 citations
Cites background from "Epigenetic codes in cognition and b..."
...[From Gräff and Mansuy (82), with permission from Elsevier....
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...[From Gräff and Mansuy (82), with permission from Elsevier.]...
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TL;DR: As histone acetylation and cognitive functions can be pharmacologically restored by histone deacetylase inhibitors, this epigenetic modification might constitute a molecular memory aid on the chromatin and, by extension, a new template for therapeutic interventions against cognitive frailty.
Abstract: Long-lasting memories require specific gene expression programmes that are, in part, orchestrated by epigenetic mechanisms. Of the epigenetic modifications identified in cognitive processes, histone acetylation has spurred considerable interest. Whereas increments in histone acetylation have consistently been shown to favour learning and memory, a lack thereof has been causally implicated in cognitive impairments in neurodevelopmental disorders, neurodegeneration and ageing. As histone acetylation and cognitive functions can be pharmacologically restored by histone deacetylase inhibitors, this epigenetic modification might constitute a molecular memory aid on the chromatin and, by extension, a new template for therapeutic interventions against cognitive frailty.
506 citations
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TL;DR: This Review develops four defining criteria that enable us to critically assess the recent progress that has been made towards finding the engram, and proposes that findings from 'capture' studies represent considerable progress in allowing us to observe, erase and express the engrams.
Abstract: Many attempts have been made to localize the physical trace of a memory, or engram, in the brain However, until recently, engrams have remained largely elusive In this Review, we develop four defining criteria that enable us to critically assess the recent progress that has been made towards finding the engram Recent 'capture' studies use novel approaches to tag populations of neurons that are active during memory encoding, thereby allowing these engram-associated neurons to be manipulated at later times We propose that findings from these capture studies represent considerable progress in allowing us to observe, erase and express the engram
464 citations
References
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TL;DR: The mouse Fused locus encodes a protein that has been implicated in the regulation of embryonic axis formation and contains regions of similarity to the RGS (regulators of G-protein signaling) family of proteins as well as to dishevelled, aprotein that acts downstream of Wingless in D. melanogaster.
Abstract: The mouse Fused locus encodes a protein that has been implicated in the regulation of embryonic axis formation. The protein, which has been named Axin to distinguish it from the product of the unrelated Drosophila melanogaster gene fused , contains regions of similarity to the RGS (regulators of G-protein signaling) family of proteins as well as to dishevelled, a protein that acts downstream of Wingless in D. melanogaster . Loss-of-function mutations at Fused lead to lethality between days 8 and 10 of gestation. Three dominant mutations result in a kinked tail in heterozygotes. Two of the dominant mutations, Fused and Knobbly , result from insertions of intracisternal A particle retrotransposons into the gene. The insertion in Fused , within the sixth intron, creates a gene that produces wild-type transcripts as well as mutant transcripts that initiate at both the authentic promoter and the 3′-most long terminal repeat of the insertion. Knobbly , an insertion of the retrotransposon into exon 7, precludes the production of wild-type protein. Thus the Fused homozygote is viable whereas Knobbly is a recessive embryonic lethal. In both mutants the dominant kink-tailed phenotype is likely to result from the synthesis of similar amino-terminal fragments of Axin protein that would contain the RGS domain, but lack the dishevelled domain.
165 citations
"Epigenetic codes in cognition and b..." refers background in this paper
...[124] Vasicek TJ, Zhen L, Guan X-J, Zhang T, Costantini F, Tilghman SM....
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...The dominant AxinFu allele ontains an IAP in intron 6, which, when expressed leads to the roduction of several aberrant RNA molecules and a kinkedail phenotype [124]....
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TL;DR: In heterozygous reeler mice, which are haploinsufficient in RELN, inhibitors of histone deacetylase increase DNA demethylase activity and restore RELN expression, and could be of therapeutic value in mitigating vulnerability to schizophrenia among high-risk individuals.
Abstract: The downregulation of the Reelin gene (RELN) that occurs in schizophrenic brains, which are characterized by pyramidal neurons with shortened dendrites and by reduced expression densities of dendritic spines, may well result from hypermethylation of the RELN promoter. In the adult mammalian brain, gamma-aminoburytic acid-secreting (GABAergic) interneurons release RELN into the extracellular matrix, where it binds with high affinity to the integrin receptors present at dendritic spine postsynaptic densities and likely plays a role, elaborated in this article, in synaptic plasticity. In heterozygous reeler mice, which are haploinsufficient in RELN, inhibitors of histone deacetylase increase DNA demethylase activity and restore RELN expression. Such inhibitors could thus be of therapeutic value in mitigating vulnerability to schizophrenia among high-risk individuals.
163 citations
"Epigenetic codes in cognition and b..." refers background in this paper
...[89] Costa E, Chen Y, Davis J, Dong E, Noh JS, Tremolizzo L, et al....
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...Recent evidence has indicated that the epigeetic downregulation of the extracellular matrix protein reelin is ausally linked to the disease (reviewed in [89])....
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TL;DR: A significant increase of the alpha synuclein promoter DNA methylation in patients with alcoholism which was significantly associated with their elevated homocysteine levels and may explain the reduced value of craving under alcohol drinking conditions.
Abstract: The aim of this study was to investigate whether the DNA methylation pattern within the alpha synuclein promoter region is altered in intoxicated and early abstinence patients with alcoholism undergoing alcohol withdrawal. We observed a significant increase of the alpha synuclein promoter DNA methylation in patients with alcoholism which was significantly associated with their elevated homocysteine levels. No significant differences of the promoter DNA methylation within a control gene (presenilin-1) in alcoholics and controls were found. The present results hint to a gene specific DNA promoter hypermethylation within the alpha synuclein gene. Since hypermethylation of DNA is an important epigenetic factor in the down regulation of gene expression and since alpha synuclein has been linked to craving these findings may explain the reduced value of craving under alcohol drinking conditions.
161 citations
"Epigenetic codes in cognition and b..." refers background in this paper
...[101] Bonsch D, Lenz B, Kornhuber J, Bleich S....
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...Alcohol addiction α-synuclein Alcohol consumption in chronic patients leads to hypermethylation of α-synuclein None suggested [101]...
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TL;DR: The results suggest that the loss of the HAT activity of CBP may cause RTS, as the first example of a defect of H AT activity in a human disease, and raise the possibility that treatment of RTS patients with histone deacetylase inhibitors might have beneficial effects.
Abstract: CREB-binding protein (CBP) is a transcriptional coactivator that has intrinsic histone acetyltransferase (HAT) activity. CBP is the causative gene of Rubinstein-Taybi syndrome (RTS). To investigate the relationships between CBP HAT activity and RTS, we analyzed 16 RTS patients. A microdeletion was identified in one patient by fluorescent in situ hybridization analysis. Heteroallelic mutations were identified in five patients by reverse transcriptase-polymerase chain reaction-single-strand conformation polymorphism analysis and sequencing. These included a 2 bp deletion between nucleotides 4319 and 4320, an 11 bp deletion between nucleotides 4898 and 4908, a 14 bp insertion (CCTCGGTCCTGCAC) between nucleotides 5212 and 5213, a 2 bp deletion between nucleotides 5222 and 5223, and a missense mutation from guanine (G) to cytosine (C) at nucleotide 4951 that changed codon 1378 from CGG (arginine) to CCG (proline). The identical missense mutation was introduced into the recombinant mouse CBP. It abolished the HAT activity of CBP and the ability of CBP to transactivate cyclic AMP-response element binding protein (CREB), in HAT assays and in microinjection experiments, respectively. These results suggest that the loss of the HAT activity of CBP may cause RTS, as the first example of a defect of HAT activity in a human disease. Our findings raise the possibility that treatment of RTS patients with histone deacetylase inhibitors might have beneficial effects.
159 citations
"Epigenetic codes in cognition and b..." refers background in this paper
...[59] Murata T, Kurokawa R, Krones A, Tatsumi K, Ishii M, Taki T, et al....
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TL;DR: Some of the questions currently debated in the field of memory consolidation and reconsolidation, the molecular and anatomical requirements for both processes and, finally, their functional relationship are discussed.
Abstract: Memories become stabilized through a time-dependent process that requires gene expression and is commonly known as consolidation. During this time, memories are labile and can be disrupted by a number of interfering events, including electroconvulsive shock, trauma and other learning or the transient effect of drugs such as protein synthesis inhibitors. Once consolidated, memories are insensitive to these disruptions. However, they can again become fragile if recalled or reactivated. Reactivation creates another time-dependent process, known as reconsolidation, during which the memory is restabilized. Here we discuss some of the questions currently debated in the field of memory consolidation and reconsolidation, the molecular and anatomical requirements for both processes and, finally, their functional relationship.
156 citations
"Epigenetic codes in cognition and b..." refers background in this paper
...[145] Alberini CM, Milekic MH, Tronel S....
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...owever, this may be difficult to be reconciled with the conept of retrieval/reconsolidation, during which a memory trace s temporarily destabilized when retrieved, then reconsolidated or further maintenance (for a review see [145])....
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