Methionine increases BDNF DNA methylation and improves memory in epilepsy

Abstract

ObjectiveTemporal 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 learning-induced transcription of memory-permissive genes in the epileptic hippocampus.MethodsUsing 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.ResultsWe found that behaviorally driven BdnfDNA methylation was associated with hippocampus-dependent memory deficits. Bisulfite sequencing revealed that decreased BdnfDNA methylation levels strongly correlated with abnormally high levels of BdnfmRNA in the epileptic hippocampus during memory consolidation. Methyl supplementation via methionine (Met) increased BdnfDNA methylation and reduced BdnfmRNA 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 BdnfDNA methylation, Bdnf gene expression, and hippocampus-dependent memory, were attenuated by DNA methyltransferase blockade.InterpretationOur 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.

Early micronutrient supplementation protects against early stress‐induced cognitive impairments

“…Our finding of no alterations in global DNA methylation levels might be a result of the fact that central levels of the other measured 1‐CMAM are unaffected by ES. These are further supported by evidence that both maternal care and acute methionine administration in a model of epilepsy failed to alter global DNA methylation in the hippocampus (12, 52).…”

“…Of interest, effects of methionine supplementation during adulthood have been reported before, although these were administered for a prolonged period of time under depletion conditions‐for instance, severe adult folate deficiency induced cognitive impairments that could be prevented by a prolonged dietary methionine supplementation (47). In addition, also highlighting the powerful properties of these nutrients under specific conditions, acute or prolonged administration of methionine or the universal methyl donor S‐adenosyl methionine during adulthood rescued cognitive impairments that were a result of earlier epilepsy or lead or cocaine exposure (12, 48–52) and improved drug‐seeking behaviors (53). Our results show the sensitivity of specific nutrients to ES exposure and highlight a key role for them during early life in long‐term brain programming, as well as the efficacy of early nutritional interventions to prevent later ES‐induced effects on cognition.…”

Methyl donor supplementation in rats reverses the deleterious effect of maternal separation on depression-like behaviour

“…Our group has previously reported a significant decrease in hippocampal BDNF expression in the same rat model of 3-hour daily maternal separation [44]. A recent study has reported that methyl supplementation via methionine is able to increase BDNF DNA methylation and reduce BDNF mRNA levels in the hippocampus of epileptic rats during memory consolidation, reversing memory deficits in these animals [45]. This result suggests that methyl donor supplementation as performed in our study (extra folic acid, vitamin B12, betaine and choline) could also be able to reverse the detrimental effects of early life stress on BDNF methylation and expression in rat hippocampus, although more studies are required.…”

Comparison of the Adulthood Chronic Stress Effect on Hippocampal BDNF Signaling in Male and Female Rats

“…DNA methylation is one factor that involved in epigenetic modulation and tends to silence genes [43]. In the current study, we assessed DNA methylation levels in the exon IV of BDNF transcripts based on the fact that exon IV is the primary BDNF exon responsible for activity-dependent BDNF mRNA expression [44][45][46]. As well, it is known that environment-induced changes in BDNF gene expression correlated with DNA methylation of exon IV.…”