Methionine increases BDNF DNA methylation and improves memory in epilepsy

Academic Article

Abstract

  • © 2015 The Authors. Objective: Temporal lobe epilepsy (TLE) patients exhibit signs of memory impairments even when seizures are pharmacologically controlled. Surprisingly, the underlying molecular mechanisms involved in TLE-associated memory impairments remain elusive. Memory consolidation requires epigenetic transcriptional regulation of genes in the hippocampus; therefore, we aimed to determine how epigenetic DNA methylation mechanisms affect learninginduced transcription of memory-permissive genes in the epileptic hippocampus. Methods: Using the kainate rodent model of TLE and focusing on the brain-derived neurotrophic factor (Bdnf) gene as a candidate of DNA methylation- mediated transcription, we analyzed DNA methylation levels in epileptic rats following learning. After detection of aberrant DNA methylation at the Bdnf gene, we investigated functional effects of altered DNA methylation on hippocampus-dependent memory formation in our TLE rodent model. Results: We found that behaviorally driven Bdnf DNA methylation was associated with hippocampus-dependent memory deficits. Bisulfite sequencing revealed that decreased Bdnf DNA methylation levels strongly correlated with abnormally high levels of Bdnf mRNA in the epileptic hippocampus during memory consolidation. Methyl supplementation via methionine (Met) increased Bdnf DNA methylation and reduced Bdnf mRNA levels in the epileptic hippocampus during memory consolidation. Met administration reduced interictal spike activity, increased theta rhythm power, and reversed memory deficits in epileptic animals. The rescue effect of Met treatment on learning-induced Bdnf DNA methylation, Bdnf gene expression, and hippocampus-dependent memory, were attenuated by DNA methyltransferase blockade. Interpretation: Our findings suggest that manipulation of DNA methylation in the epileptic hippocampus should be considered as a viable treatment option to ameliorate memory impairments associated with TLE.
  • Authors

    Digital Object Identifier (doi)

    Author List

  • Parrish RR; Buckingham SC; Mascia KL; Johnson JJ; Matyjasik MM; Lockhart RM; Lubin FD
  • Volume

  • 2
  • Issue

  • 4