Status epilepticus triggers early and late alterations in brain-derived neurotrophic factor and NMDA glutamate receptor Grin2b DNA methylation levels in the hippocampus

Abstract

Status epilepticus (SE) triggers abnormal expression of genes in the hippocampus, such as glutamate receptor subunit epsilon-2 (Grin2b/Nr2b) and brain-derived neurotrophic factor (Bdnf), that is thought to occur in temporal lobe epilepsy (TLE). We examined the underlying DNA methylation mechanisms and investigated whether these mechanisms contribute to the expression of these gene targets in the epileptic hippocampus. Experimental TLE was provoked by kainic acid-induced SE. Bisulfite sequencing analysis revealed increased Grin2b/Nr2b and decreased Bdnf DNA methylation levels that corresponded to decreased Grin2b/Nr2b and increased Bdnf mRNA and protein expression in the epileptic hippocampus. Blockade of DNA methyltransferase (DNMT) activity with zebularine decreased global DNA methylation levels and reduced Grin2b/Nr2b, but not Bdnf, DNA methylation levels. Interestingly, we found that DNMT blockade further decreased Grin2b/Nr2b mRNA expression whereas GRIN2B protein expression increased in the epileptic hippocampus, suggesting that a posttranscriptional mechanism may be involved. Using chromatin immunoprecipitation analysis we found that DNMT inhibition restored the decreases in AP2alpha transcription factor levels at the Grin2b/Nr2b promoter in the epileptic hippocampus. DNMT inhibition increased field excitatory postsynaptic potential in hippocampal slices isolated from epileptic rats. EEG monitoring confirmed that DNMT inhibition did not significantly alter disease course, but promoted the latency to seizure onset or SE. Thus, DNA methylation may be an early event triggered by SE that persists late into the epileptic hippocampus to contribute to gene expression changes in TLE.

Elevation of Peripheral BDNF Promoter Methylation Links to the Risk of Alzheimer's Disease

“…Decreased BDNF promoter methylation levels were shown to be correlated with increased BDNF mRNA and protein expression in the epileptic hippocampus [49]. Reductions of BDNF protein in frozen postmortem AD frontal cortex samples compared to controls showed reduced mRNA levels of BDNF , which might be related to the hypermethylated BDNF promoter in the same tissues [24].…”

Detection of global DNA hypomethylation of peripheral blood lymphocytes in patients with infantile spasms

“…The imprinting defects in chromosome 15q11.2-q13 region that causes Angelman syndrome is also closely associated with DNA methylation (Dagli et al, 2012). Moreover, the dynamic epigenetic modification of hippocampal brain derived neurotrophic factor DNA was also found in the rat model of status epilepticus (Ryley Parrish et al, 2013).…”

Epigenetics and Epilepsy

“…Adenosine augmentation .10 days reversed DNA hypermethylation seen in the epileptic brain, inhibited hippocampal sprouting of mossy fibers, and prevented the progression of epilepsy for at least 3 months (Williams-Karnesky et al 2013). However, pharmacological inhibition of DNA methylation was not found to alter epilepsy in another recent study (Ryley Parrish et al 2013). Nevertheless, these data suggest that DNA methylation is involved in epileptogenesis and propagation of the chronic disease state, accounting for the synergistic misregulation of multiple genes.…”

“…A number of genes previously associated with neuronal hyperactivity and seizures in vitro and in vivo have been described with altered DNA methylation profiles in their promoters including Bdnf, Gria2, and Grin2b (Martinowich et al 2003;Machnes et al 2013;Ryley Parrish et al 2013). There is further evidence for aberrant DNA methylation of the Reelin (RELN) promoter associated with granule cell dispersion, a frequent migration defect targeting the hippocampal granule cell layer, in temporal lobe epilepsy (TLE) patients with hippocampal sclerosis (Kobow et al 2009).…”