title: Inhibition of DNA Methylation Impairs Synaptic Plasticity during an Early Time Window in Rats.
abstract: Although the importance of DNA methylation-dependent gene expression to neuronal plasticity is well established, the dynamics of methylation and demethylation during the induction and expression of synaptic plasticity have not been explored. Here, we combined electrophysiological, pharmacological, molecular, and immunohistochemical approaches to examine the contribution of DNA methylation and the phosphorylation of Methyl-CpG-binding protein 2 (MeCP2) to synaptic plasticity. We found that, at twenty minutes after theta burst stimulation (TBS), the DNA methylation inhibitor 5-aza-2-deoxycytidine (5AZA) impaired hippocampal long-term potentiation (LTP). Surprisingly, after two hours of TBS, when LTP had become a transcription-dependent process, 5AZA treatment had no effect. By comparing these results to those in naive slices, we found that, at two hours after TBS, an intergenic region of the RLN gene was hypomethylated and that the phosphorylation of residue S80 of MeCP2 was decreased, while the phosphorylation of residue S421 was increased. As expected, 5AZA affected only the methylation of the RLN gene and exerted no effect on MeCP2 phosphorylation patterns. In summary, our data suggest that tetanic stimulation induces critical changes in synaptic plasticity that affects both DNA methylation and the phosphorylation of MeCP2. These data also suggest that early alterations in DNA methylation are sufficient to impair the full expression of LTP.
authors: Department of Pathology and Physiology, School of Medicine, Faculty of Medicine, University of Valparaíso, 2341386 Valparaíso, Chile; Interdisciplinary Center for Innovation in Health (CIIS), University of Valparaíso, 8380492 Valparaíso, Chile.
authors: Pablo
authors: 0000-0002-2856-0654
authors: P
authors: Muñoz
authors: Department of Pathology and Physiology, School of Medicine, Faculty of Medicine, University of Valparaíso, 2341386 Valparaíso, Chile.
authors: Carolina
authors: 0000-0003-3703-9526
authors: C
authors: Estay
authors: Department of Pathology and Physiology, School of Medicine, Faculty of Medicine, University of Valparaíso, 2341386 Valparaíso, Chile.
authors: Paula
authors: P
authors: Díaz
authors: Institute of Physiology I, Systemic and Cellular Neuroscience, Albert-Ludwigs University Freiburg, 79104 Freiburg im Breisgau, Germany.
authors: Claudio
authors: 0000-0001-8256-8967
authors: C
authors: Elgueta
authors: Department of Pathology and Physiology, School of Medicine, Faculty of Medicine, University of Valparaíso, 2341386 Valparaíso, Chile; Interdisciplinary Center for Innovation in Health (CIIS), University of Valparaíso, 8380492 Valparaíso, Chile; CINV-Universidad de Valparaíso, 2360102 Valparaíso, Chile.
authors: Álvaro O
authors: ÁO
authors: Ardiles
authors: Instituto de Biología, Pontificia Universidad Católica de Valparaíso, 3100000 Valparaíso, Chile.
authors: Pablo A
authors: 0000-0002-9366-6930
authors: PA
authors: Lizana
mesh_terms: D000367:Age Factors; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects / Q000502:physiology*; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004791:Enzyme Inhibitors; C497394:Mecp2 protein, rat; D051783:Methyl-CpG-Binding Protein 2; D000077209:Decitabine; D001374:Azacitidine