TY - JOUR
T1 - Effects of DNA methyltransferase inhibition on pattern separation performance in mice
AU - Argyrousi, Elentina K.
AU - de Nijs, Laurence
AU - Lagatta, Davi C.
AU - Schlütter, Anna
AU - Weidner, Magdalena T.
AU - Zoeller, Johanna
AU - van Goethem, Nick P.
AU - Joca, Samia R. L.
AU - van den Hove, Daniel L. A.
AU - Prickaerts, Jos
N1 - Funding Information:
LdN has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement [707362]. DL and SJ were funded by a grant from CAPES/NUFFIC [015/10; Brazil]. In addition, SJ was supported by a research productivity fellowship from the National Council of Science and Technology [CNPq; Brazil]. DLAvdH was supported by the Deutsche Forschungsgemeinschaft (DFG) Sonderforschungsbereich Transregio (SFB TRR) [58/A5; Germany].
Funding Information:
LdN has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement [707362]. DL and SJ were funded by a grant from CAPES/NUFFIC [015/10; Brazil]. In addition, SJ was supported by a research productivity fellowship from the National Council of Science and Technology [CNPq; Brazil]. DLAvdH was supported by the Deutsche Forschungsgemeinschaft (DFG) Sonderforschungsbereich Transregio (SFB TRR) [58/A5; Germany].
Publisher Copyright:
© 2019
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 - BDNF MESSENGER-RNA
KW - CONSOLIDATION
KW - CpG islands
KW - DENTATE GYRUS
KW - DNA methyltransferase inhibitors
KW - EPIGENETIC REGULATION
KW - EXPRESSION
KW - Epigenetics
KW - HIPPOCAMPAL LTP
KW - Hippocampal plasticity
KW - METHYLATION
KW - NEUROTROPHIC FACTOR
KW - Object pattern separation
KW - SUBCELLULAR-LOCALIZATION
KW - TRANSCRIPTION
U2 - 10.1016/j.nlm.2019.02.003
DO - 10.1016/j.nlm.2019.02.003
M3 - 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 -