Effects of DNA methyltransferase inhibition on pattern separation performance in mice

• Published in: Neurobiology of learning and memory 2019-03, Vol.159, p.6-15
• Main Authors: Argyrousi, Elentina K., de Nijs, Laurence, Lagatta, Davi C., Schlütter, Anna, Weidner, Magdalena T., Zöller, Johanna, van Goethem, Nick P., Joca, Sâmia R.L., van den Hove, Daniel L.A., Prickaerts, Jos
• Format: Article
• Language: English
• Subjects: Animals; BDNF; Behavior, Animal - drug effects; CpG islands; CpG Islands - drug effects; DNA (Cytosine-5-)-Methyltransferases - antagonists & inhibitors; DNA methyltransferase inhibitors; Enzyme Inhibitors - pharmacology; Epigenesis, Genetic - drug effects; Epigenetics; Exploratory Behavior - drug effects; Gene Expression - drug effects; Hippocampal plasticity; Hippocampus - drug effects; Memory, Long-Term - drug effects; Memory, Short-Term - drug effects; Mice; Minute Virus of Mice; Neuronal Plasticity - drug effects; Object pattern separation; Phthalimides - pharmacology; Promoter Regions, Genetic - drug effects; Space Perception - drug effects; Tryptophan - analogs & derivatives; Tryptophan - pharmacology
• ISSN: 1074-7427; 1095-9564
• DOI: 10.1016/j.nlm.2019.02.003

•Acute DNMT inhibition improves short-term object pattern separation memory.•Acute DNMT inhibition does not affect long-term object pattern separation memory.•DNMT inhibition increases Bdnf1 expression in dorsal hippocampi of mice.•DNMT inhibition increases methylation in three CpG islands at Bdnf1 promoter. 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.