Article

Epigenetics and epilepsy

Epilepsia (Impact Factor: 4.57). 12/2012; 53(s9). DOI: 10.1111/epi.12030

ABSTRACT

Seizures can give rise to enduring changes that reflect alterations in gene-expression patterns, intracellular and intercellular signaling, and ultimately network alterations that are a hallmark of epilepsy. A growing body of literature suggests that long-term changes in gene transcription associated with epilepsy are mediated via modulation of chromatin structure. One transcription factor in particular, repressor element 1-silencing transcription factor (REST), has received a lot of attention due to the possibility that it may control fundamental transcription patterns that drive circuit excitability, seizures, and epilepsy. REST represses a suite of genes in the nervous system by utilizing nuclear protein complexes that were originally identified as mediators of epigenetic inheritance. Epigenetics has traditionally referred to mechanisms that allow a heritable change in gene expression in the absence of DNA mutation. However a more contemporaneous definition acknowledges that many of the mechanisms used to perpetuate epigenetic traits in dividing cells are utilized by neurons to control activity-dependent gene expression. This review surveys what is currently understood about the role of epigenetic mechanisms in epilepsy. We discuss how REST controls gene expression to affect circuit excitability and neurogenesis in epilepsy. We also discuss how the repressor methyl-CpG-binding protein 2 (MeCP2) and activator cyclic AMP response element binding protein (CREB) regulate neuronal activity and are themselves controlled by activity. Finally we highlight possible future directions in the field of epigenetics and epilepsy.

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Available from: Raymond Dingledine, Jan 06, 2016
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    • "On the other hand, under pathological conditions, epigenetic dynamics are thought to represent wide-scale alterations in the expression of multiple genes (Grote et al., 2015). Furthermore, it is well known that seizures can give rise to enduring changes that reflect alterations in gene expression patterns that contribute to the hallmarks of epilepsy (Roopra et al., 2012). Currently, a few reports have studied specific markers of epigenetic mechanisms in both acute seizures and epilepsy models per se, and even more studies have used a metabolism-based diet. "
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    ABSTRACT: A new generation of antiepileptic drugs has emerged; however, one-third of epilepsy patients do not properly respond to pharmacological treatments. The purpose of the present study was to investigate whether time-restricted feeding has an anticonvulsant effect and whether this restrictive diet promotes changes in energy metabolism and epigenetic modifications in a pilocarpine-induced seizure model. To resolve our hypothesis, one group of rats had free access to food and water ad libitum (AL) and a second group underwent a time-restricted feeding (TRF) schedule. We used the lithium-pilocarpine model to induce status epilepticus (SE), and behavioral seizure monitoring was analyzed. Additionally, an electroencephalography (EEG) recording was performed to verify the effect of TRF on cortical electrical activity after a pilocarpine injection. For biochemical analysis, animals were sacrificed 24 hours after SE and hippocampal homogenates were used to evaluate the proteins related to metabolism and chromatin structure. Our results showed that TRF had an anticonvulsant effect as measured by the prolonged latency of forelimb clonus seizure, a decrease in the seizure severity score and fewer animals reaching SE. Additionally, the power of the late phase EEG recordings in the AL group was significantly higher than the TRF group. Moreover, we found that TRF is capable of inducing alterations in signaling pathways that regulate energy metabolism, including an increase in the phosphorylation of AMP dependent kinase (AMPK) and a decrease in the phosphorylation of Akt kinase. Furthermore, we found that TRF was able to significantly increase the beta hydroxybutyrate (β-HB) concentration, an endogenous inhibitor of histone deacetylases (HDACs). Finally, we found a significant decrease in HDAC activity as well as an increase in acetylation on histone 3 (H3) in hippocampal homogenates from the TRF group. These findings suggest that alterations in energy metabolism and the increase in β-HB mediated by TRF may inhibit HDAC activity, thus increasing histone acetylation and producing changes in the chromatin structure, which likely facilitates the transcription of a subset of genes that confer anticonvulsant activity.
    Full-text · Article · Feb 2016 · Frontiers in Cellular Neuroscience
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    • "Repressor element-1 silencing transcription factor and neuronal restrictive silencer factor serve to repress gene expression through dynamic recruitment of epigenetic complexes (Qureshi and Mehler, 2009). Of interest, repressor element-1 silencing transcription has been implicated in the regulation of several epileptogenesis specific factors, including growth factors, neurotransmitter receptors, ion channels, circuit excitability, and neurogenesis (Huang et al., 1999; McClelland et al., 2011a,b; Roopra et al., 2012). "
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    • "There was also a 20–25% reduction in parvalbumin and NPY interneurons in the striatum. MECP2, the gene responsible for Rett syndrome and one of the first genes to be linked to ASD, is also associated with seizures, though these seizure with Rett syndrome typically occur later in life (Roopra et al., 2012). This variable timing between the onset of encephalopathy and of epilepsy seen across different genetic lesions argues that the encephalopathy and seizures are each products of the gene defect occurring independently rather than one being the consequence of the other. "
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