Effects of DNA methyltransferase inhibition on pattern separation performance in mice.

EK Argyrousi; DC Lagatta; A Schulutter; MT Weidner; J Zoller; NP van Goethem; Sâmia Joca; DLA van den Hove; J Prickaerts

doi:10.1016/j.nlm.2019.02.003

Effects of DNA methyltransferase inhibition on pattern separation performance in mice.

EK Argyrousi, DC Lagatta, A Schulutter, MT Weidner, J Zoller, NP van Goethem, Sâmia Joca, DLA van den Hove, J Prickaerts

Department of Clinical Medicine - Translational Neuropsychiatry Unit

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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Abstract

Enhancement of synaptic plasticity through changes in neuronal gene expression is a prerequisite for improved cognitive performance. Moreover, several studies have shown that DNA methylation is able to affect the expression of (e.g. plasticity) genes that are important for several cognitive functions. In this study, the effect of the DNA methyltransferase (DNMT) inhibitor RG108 was assessed on object pattern separation (OPS) task in mice. In addition, its effect on the expression of target genes was monitored. Administration of RG108 before the test led to a short-lasting, dose-dependent increase in pattern separation memory that was not present anymore after 48 h. Furthermore, treatment with RG108 did not enhance long-term memory of the animals when tested after a 24 h inter-trial interval in the same task. At the transcriptomic level, acute treatment with RG108 was accompanied by increased expression of Bdnf1, while expression of Bdnf4, Bdnf9, Gria1 and Hdac2 was not altered within 1 h after treatment. Methylation analysis of 14 loci in the promoter region of Bdnf1 revealed a counterintuitive increase in the levels of DNA methylation at three CpG sites. Taken together, these results indicate that acute administration of RG108 has a short-lasting pro-cognitive effect on object pattern separation that could be explained by increased Bdnf1 expression. The observed increase in Bdnf1 methylation suggests a complex interplay between Bdnf methylation-demethylation that promotes Bdnf1 expression and associated cognitive performance. Considering that impaired pattern separation could constitute the underlying problem of a wide range of mental and cognitive disorders, pharmacological agents including DNA methylation inhibitors that improve pattern separation could be compelling targets for the treatment of these disorders. In that respect, future studies are needed in order to determine the effect of chronic administration of such agents.

Original language	English
Journal	Neurobiology of Learning and Memory
Volume	159
Pages (from-to)	6-15
Number of pages	9
ISSN	1074-7427
DOIs	https://doi.org/10.1016/j.nlm.2019.02.003
Publication status	Published - Mar 2019

Keywords

BDNF
CpG islands
DNA methyltransferase inhibitors
Epigenetics
Hippocampal plasticity
Object pattern separation

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title = "Effects of DNA methyltransferase inhibition on pattern separation performance in mice.",

abstract = "Enhancement of synaptic plasticity through changes in neuronal gene expression is a prerequisite for improved cognitive performance. Moreover, several studies have shown that DNA methylation is able to affect the expression of (e.g. plasticity) genes that are important for several cognitive functions. In this study, the effect of the DNA methyltransferase (DNMT) inhibitor RG108 was assessed on object pattern separation (OPS) task in mice. In addition, its effect on the expression of target genes was monitored. Administration of RG108 before the test led to a short-lasting, dose-dependent increase in pattern separation memory that was not present anymore after 48 h. Furthermore, treatment with RG108 did not enhance long-term memory of the animals when tested after a 24 h inter-trial interval in the same task. At the transcriptomic level, acute treatment with RG108 was accompanied by increased expression of Bdnf1, while expression of Bdnf4, Bdnf9, Gria1 and Hdac2 was not altered within 1 h after treatment. Methylation analysis of 14 loci in the promoter region of Bdnf1 revealed a counterintuitive increase in the levels of DNA methylation at three CpG sites. Taken together, these results indicate that acute administration of RG108 has a short-lasting pro-cognitive effect on object pattern separation that could be explained by increased Bdnf1 expression. The observed increase in Bdnf1 methylation suggests a complex interplay between Bdnf methylation-demethylation that promotes Bdnf1 expression and associated cognitive performance. Considering that impaired pattern separation could constitute the underlying problem of a wide range of mental and cognitive disorders, pharmacological agents including DNA methylation inhibitors that improve pattern separation could be compelling targets for the treatment of these disorders. In that respect, future studies are needed in order to determine the effect of chronic administration of such agents.",

keywords = "BDNF, CpG islands, DNA methyltransferase inhibitors, Epigenetics, Hippocampal plasticity, Object pattern separation",

author = "EK Argyrousi and DC Lagatta and A Schulutter and MT Weidner and J Zoller and {van Goethem}, NP and S{\^a}mia Joca and {van den Hove}, DLA and J Prickaerts",

year = "2019",

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doi = "10.1016/j.nlm.2019.02.003",

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T1 - Effects of DNA methyltransferase inhibition on pattern separation performance in mice.

AU - Argyrousi, EK

AU - Lagatta, DC

AU - Schulutter, A

AU - Weidner, MT

AU - Zoller, J

AU - van Goethem, NP

AU - Joca, Sâmia

AU - van den Hove, DLA

AU - Prickaerts, J

PY - 2019/3

Y1 - 2019/3

N2 - Enhancement of synaptic plasticity through changes in neuronal gene expression is a prerequisite for improved cognitive performance. Moreover, several studies have shown that DNA methylation is able to affect the expression of (e.g. plasticity) genes that are important for several cognitive functions. In this study, the effect of the DNA methyltransferase (DNMT) inhibitor RG108 was assessed on object pattern separation (OPS) task in mice. In addition, its effect on the expression of target genes was monitored. Administration of RG108 before the test led to a short-lasting, dose-dependent increase in pattern separation memory that was not present anymore after 48 h. Furthermore, treatment with RG108 did not enhance long-term memory of the animals when tested after a 24 h inter-trial interval in the same task. At the transcriptomic level, acute treatment with RG108 was accompanied by increased expression of Bdnf1, while expression of Bdnf4, Bdnf9, Gria1 and Hdac2 was not altered within 1 h after treatment. Methylation analysis of 14 loci in the promoter region of Bdnf1 revealed a counterintuitive increase in the levels of DNA methylation at three CpG sites. Taken together, these results indicate that acute administration of RG108 has a short-lasting pro-cognitive effect on object pattern separation that could be explained by increased Bdnf1 expression. The observed increase in Bdnf1 methylation suggests a complex interplay between Bdnf methylation-demethylation that promotes Bdnf1 expression and associated cognitive performance. Considering that impaired pattern separation could constitute the underlying problem of a wide range of mental and cognitive disorders, pharmacological agents including DNA methylation inhibitors that improve pattern separation could be compelling targets for the treatment of these disorders. In that respect, future studies are needed in order to determine the effect of chronic administration of such agents.

AB - Enhancement of synaptic plasticity through changes in neuronal gene expression is a prerequisite for improved cognitive performance. Moreover, several studies have shown that DNA methylation is able to affect the expression of (e.g. plasticity) genes that are important for several cognitive functions. In this study, the effect of the DNA methyltransferase (DNMT) inhibitor RG108 was assessed on object pattern separation (OPS) task in mice. In addition, its effect on the expression of target genes was monitored. Administration of RG108 before the test led to a short-lasting, dose-dependent increase in pattern separation memory that was not present anymore after 48 h. Furthermore, treatment with RG108 did not enhance long-term memory of the animals when tested after a 24 h inter-trial interval in the same task. At the transcriptomic level, acute treatment with RG108 was accompanied by increased expression of Bdnf1, while expression of Bdnf4, Bdnf9, Gria1 and Hdac2 was not altered within 1 h after treatment. Methylation analysis of 14 loci in the promoter region of Bdnf1 revealed a counterintuitive increase in the levels of DNA methylation at three CpG sites. Taken together, these results indicate that acute administration of RG108 has a short-lasting pro-cognitive effect on object pattern separation that could be explained by increased Bdnf1 expression. The observed increase in Bdnf1 methylation suggests a complex interplay between Bdnf methylation-demethylation that promotes Bdnf1 expression and associated cognitive performance. Considering that impaired pattern separation could constitute the underlying problem of a wide range of mental and cognitive disorders, pharmacological agents including DNA methylation inhibitors that improve pattern separation could be compelling targets for the treatment of these disorders. In that respect, future studies are needed in order to determine the effect of chronic administration of such agents.

KW - BDNF

KW - CpG islands

KW - DNA methyltransferase inhibitors

KW - Epigenetics

KW - Hippocampal plasticity

KW - Object pattern separation

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DO - 10.1016/j.nlm.2019.02.003

M3 - Journal article

C2 - 30731235

SN - 1074-7427

VL - 159

SP - 6

EP - 15

JO - Neurobiology of Learning and Memory

JF - Neurobiology of Learning and Memory

ER -

Effects of DNA methyltransferase inhibition on pattern separation performance in mice.

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Keywords

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