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

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  • EK Argyrousi, Maastricht University, Maastricht, Netherlands
  • DC Lagatta, Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Brazil., Brazil
  • A Schulutter, Maastricht University, Maastricht, Netherlands
  • MT Weidner, Maastricht University, Maastricht, Netherlands
  • J Zoller, University of Würzburg, Netherlands
  • NP van Goethem, Maastricht University, Maastricht, Netherlands
  • Sâmia Joca
  • DLA van den Hove, Maastricht Univ, Maastricht University, CARIM, Dept Pathol, Netherlands
  • J Prickaerts, Maastricht University, Maastricht, Netherlands
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 languageEnglish
JournalNeurobiology of Learning and Memory
Volume159
Pages (from-to)6-15
Number of pages9
ISSN1074-7427
DOIs
Publication statusPublished - Mar 2019

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