Epilepsy is a common brain disease that can cause disabling seizures. During a seizure, brain cells send out abnormal signals, which can mean that people having seizures may be unaware of their surroundings and may fall or otherwise injure themselves.

Individuals with epilepsy develop changes in their brain cells and in the circuits that connect these cells together. Some people develop epilepsy because they have mutations in genes. Others develop the condition after an injury or a long seizure, which leads to changes in gene expression and therefore changes to the brain's cells and circuits.

In 2011, researchers found that a protein that normally switches off the expression of certain genes during brain development, but which is almost absent in the adult brain, may run amok after a seizure. The level of this protein—a transcription factor called NRSF—increased in the brains of rats that had been caused to have a seizure. A long provoked seizure caused many of the rats to develop epilepsy. But, if NRSF was blocked after the original seizure, the rats were less likely to have further seizures later on. Now McClelland et al., including several of the researchers involved in the 2011 work, have examined what normally happens to the expression of genes after a seizure and what happens when the NRSF transcription factor is blocked.

McClelland et al. found that only a small subset—about 10%—of the genes that can theoretically be silenced by NRSF are switched off in the brain when this protein's levels increase after a seizure. The increased NRSF levels, unexpectedly, did not affect the genes that bind tightly to this transcription factor. Nor did NRSF affect genes that bind loosely. Instead, the genes that the transcription factor binds to with an intermediate strength were the ones that were switched off. McClelland et al. suggest that this ‘mid-range binding’ to NRSF allows the expression of these genes to be increased or decreased in response to there being more or less NRSF in the cell. Genes that bind tightly to NRSF are likely to already have a lot of NRSF bound and are therefore already switched off; and loosely-binding genes would likely need even more NRSF before they are switched off.

The subset of genes that were switched off by the increased levels of NRSF after a seizure code for a number of proteins that brain cells need to be able to effectively send and receive messages. Blocking the ability of NRSF to bind to these genes and switch them off may help to prevent the brain changes that cause epilepsy.

Epileptic networks arise via numerous mechanisms (Pitkänen et al., 2011; Vezzani et al., 2011; Kim et al., 2012; Hildebrand et al., 2013; Rowley and Patel, 2013). Changes in neuronal properties and resulting alterations of network behavior constitute one of the important mechanisms of epileptogenesis (Yaari and Beck, 2002; Noam et al., 2011; Goldberg and Coulter, 2013). Neuronal properties may change because of genetic mutations in crucial neuronal genes (Meisler and O'Brien, 2012; Oliva et al., 2012; Kingwell, 2013; Papale et al., 2013) or from insult-related alterations of gene expression that affect the levels and function of their products. Whereas altered expression of individual ion channels (Brewster et al., 2002; Khirug et al., 2010; Poolos, 2012; van Loo et al., 2012; Maslarova et al., 2013; Shah et al., 2013), neurotransmitter receptors (Gonzalez et al., 2013; Rojas and Dingledine, 2013), and other cellular components (Zeng et al., 2009; Maroso et al., 2011; Jimenez-Mateos et al., 2012; Liu et al., 2013) have been extensively reported, the nature and mechanisms of the orchestration of these gene expression changes remain unknown: do epilepsy-provoking insults regulate individual genes via distinct cellular pathways? Alternatively, are there clusters of genes that are co-regulated based on specific common properties, and whose altered expression contributes to the generation of ‘epileptic neurons’? (Brooks-Kayal et al., 2009; McClelland et al., 2011b; Kobow and Blümcke, 2012; Roopra et al., 2012; van Loo et al., 2012). These questions are critical for the understanding and future prevention of certain epilepsies.

Gene expression is dynamically regulated throughout life and influences neuronal phenotype and behavior (Bale et al., 2010; Robison and Nestler, 2011; Sweatt, 2013). This dynamic regulation is mediated by transcriptional enhancers and repressors that bind to specific sequences of target genes and modify their expression (Ballas et al., 2005; Kohyama et al., 2008; Hwang et al., 2010). The repressor neuron-restrictive silencer factor (NRSF/ REST) functions by binding a DNA sequence called neuron-restrictive silencer element (NRSE) to mediate long-term, cell-specific gene repression (Schoenherr and Anderson, 1995) via complex interactions with co-repressors such as mSin3 and Co-Rest (Chen et al., 1998; Andres et al., 1999; Naruse et al., 1999; Roopra et al., 2001; Wood et al., 2003; Belyaev et al., 2004; Kuwabara et al., 2004; Mortazavi et al., 2006; Johnson et al., 2007; Abrajano et al., 2009). NRSF is highly expressed in non-neuronal tissues where it represses neuronal genes (Ballas and Mandel, 2005) and has important roles in neurogenesis and neuronal differentation within the brain (Hsieh et al., 2004; Singh et al., 2008; Westbrook et al., 2008; Mandel et al., 2011; Aoki et al., 2012; Ernsberger, 2012; Kok et al., 2012; Rodenas-Ruano et al., 2012).

NRSF levels are low in mature hippocampus where ∼600 expressed genes contain NRSEs and are thus potentially regulated by the repressor. Hippocampal NRSF expression increases several-fold following seizures (Palm et al., 1998; Garriga-Canut et al., 2006; McClelland et al., 2011a) and following other insults that promote epilepsy (Calderone et al., 2003; Noh et al., 2012; Kaneko et al., 2014). We found that blocking NRSF function attenuated the epileptic phenotype induced by severe seizures (McClelland et al., 2011a). However, it is unclear ‘how’ augmented NRSF levels promote selective neuronal phenotypic changes that provoke epilepsy. In this study, we used large-scale transcriptome arrays, qPCR validation, chromatin immunoprecipitation (ChIP), and gene set enrichment analysis (GSEA) to examine the basis of NRSF-dependent gene expression changes during epileptogenesis. Surprisingly, a twofold to threefold increase of NRSF levels, induced by epilepsy-provoking seizures, led to repression of only a subset of potentially regulated genes, and these were rescued by interfering with NRSF function. Unexpectedly, genes found to be regulated by NRSF were characterized by mid-range NRSF-binding probabilities during the naive state. This moderate baseline binding enabled a significant increase of NRSF binding to these genes upon modest increases in NRSF tissue levels. NRSF-regulated hippocampal genes included ion channels, receptors, calcium-related molecules, and other transcription factors that govern neuronal function and plasticity, suggesting that their repression might contribute to the pathogenesis of epilepsy.

The key findings of these studies are: (1) NRSF contributes to epileptogenesis by regulating a group of genes that critically influence neuronal function; (2) whereas hundreds of hippocampal genes are potential NRSF targets because they contain NRSEs, only a few dozen are actually repressed by the transcription factor in the context of seizure-induced epilepsy as evident from their rescue when the function of NRSF is blocked; (3) the basis of the selective regulation of a subset of NRSE-containing genes includes the mid-range binding frequencies of these genes to the repressor, so that moderate fluctuations in NRSF levels influence the degree of their binding to the repressor. Whereas these findings were observed in the context of epileptogenesis, a neuroplasticity that leads to disease, they may apply to a broad spectrum of physiological and pathological activity-dependent plasticities in the mature hippocampus.

NRSF is a transcription factor with protean effects. Whereas much is known about the role of this molecule in non-neuronal tissues and in neuronal differentiation, much less information is available about the function of NRSF in mature brain (Korosi et al., 2010; McClelland et al., 2011b). More recently, a protective role of NRSF has been proposed in aging and dementia (Lu et al., 2014). In addition, NRSF may be involved in neurological disorders including Huntington disease (Zuccato et al., 2007; Soldati et al., 2011) and stroke (Calderone et al., 2003; Kaneko et al., 2014).

The contribution of NRSF to epilepsy and its development (epileptogenesis) is currently the focus of intense study (Roopra et al., 2012; Goldberg and Coulter 2013; Pozzi et al., 2013). We previously found that interfering with NRSF binding to the chromatin-attenuated epileptogenesis. Interestingly, Hu et al. found that the conditional deletion of NRSF in the forebrain resulted in increased susceptibility to kindling and enhanced mossy fiber sprouting (Hu et al., 2011). The apparent discrepancy between these studies is likely a result of the significantly different approaches. Complete deletion of NRSF in ‘naive’ neurons may induce large cascades of transcriptional changes rendering neurons more susceptible to seizures. In contrast, acute disruption of NRSF function ‘after’ an epilepsy-provoking insult, as performed in our current and previous studies, provides a more direct approach to elucidate the epileptogenic functions of NRSF because it does not interfere with NRSF function prior to the epilepsy-inducing insult. This point is important also because the role of NRSF in mature neurons is not fully understood, as discussed above.

In previous studies, we focused on the rescue of a single gene coding for the ion channel HCN1 (McClelland et al., 2011a). However, whereas it was clear that NRSF likely regulated numerous additional genes that are involved in the epileptogenic process, the identity of these genes was unclear. In this study, we used large-scale transcriptome arrays and found that NRSE-containing genes were enriched among seizure-suppressed genes and that the majority of these genes were restored to control levels after treatment with decoy NRSE–ODNs. The fact that preventing the repression of (‘rescuing’) these genes led to attenuation of epilepsy strongly supports a role for these genes in the transformation of normal neurons (and neuronal networks) into epileptic ones.

Investigating the identity of these genes, we were pleased to find that the majority were already known to contribute to crucial neuronal properties, and many had been previously implicated in pathological states including epilepsy (Sloviter, 1989; Palm et al., 1999; Pathak et al., 2007; Zuccato et al., 2007; van Gassen et al., 2009; Khirug et al., 2010; Soldati et al., 2011; McClelland et al., 2011a; Nikitidou et al., 2012; Kingwell, 2013). This was not surprising, because these genes included ion channels, neurotransmitter receptors, calcium-dependent effectors, and phosphoenzymes (Pernhorst et al., 2011; Dingledine, 2012; Rodenas-Ruano et al., 2012; Maslarova et al., 2013).

Whereas NRSF-mediated repression might theoretically involve hundreds of hippocampal NRSE-containing genes, it was intriguing to discover that in fact only a small subset of detected NRSE-containing genes were repressed by seizures. Most were rescued by blocking NRSF function—as evident using a differential array that included control and insult groups as well as groups where NRSF function was blocked—thus ascertaining that genes that are repressed during epileptogenesis are indeed repressed by the augmented levels of endogenous NRSF. To our knowledge this is the first study demonstrating the specificity of NRSF-mediated gene regulation in mature hippocampus in vivo.

What might be the basis for the apparent selectivity of NRSF repression of only a minority of putative target genes? The binding of NRSF to a gene is required (though not always sufficient; [Belyaev et al., 2004]) for its repression. A number of mechanisms may influence both the degree of NRSF binding as well as the degree of its repressive effect on genes. These include the specific NRSE sequence (Mortazavi et al., 2006; Johnson et al., 2007) that is unlikely to be the cause in the current studies (Supplementary file 1A). Other important mechanisms include the interaction of NRSF with co-factors (Andres et al., 1999; Naruse et al., 1999; Wood et al., 2003; Gao et al., 2011), as well as additional, still enigmatic effects of the chromatin environment of individual genes (Belyaev et al., 2004), which might be influenced by ‘super-enhancers’ (Lovén et al., 2013; Whyte et al., 2013).

Here, we examined the binding of NRSF to hippocampal genes before and after an epilepsy-provoking insult and found significant increment in genes that were repressed by the factor. This suggested a correlation between repressor occupancy and gene repression (Hammar et al., 2014). To our surprise, basal binding of NRSF in regulated hippocampal genes was moderate. By contrast, most non-regulated genes had either high or low NRSF occupancy in naive hippocampus, with little change after an insult that augmented NRSF levels twofold to threefold. We examined our finding in mature hippocampus by comparing the binding-frequency distribution found in hippocampus to a larger set of NRSE target genes as determined by ChIP-Seq analysis (Johnson et al., 2007). Whereas many factors, as discussed above, may lead to different NRSF binding in cell lines and hippocampus, it was encouraging to find that our estimates for the relative mid-range binding of regulated genes among those expressed in hippocampus held when superimposed on a large NRSE-containing gene set (Johnson et al., 2007). Traditionally, the focus of studies on gene–repressor interaction has been on genes with the strongest binding probability (Nichols et al., 1992; Chen et al., 1998; Singh et al., 2002). However, the genes with the strongest binding for NRSF would likely be constitutively bound to—and suppressed by—NRSF. These genes are unlikely to respond to moderate changes in NRSF levels. Rather, relatively modest seizure-induced changes in the tissue levels of NRSF regulate a subset of NRSE-containing genes that fall within a moderate ‘dynamic range’ of NRSF binding probabilities. This concept may be important for other forms of insult-induced plasticity in the mature brain including ischemia (Noh et al., 2012; Kaneko et al., 2014), peripheral nerve injury (Uchida et al., 2010), and seizure-induced epilepsy (McClelland et al., 2011a; Goldberg and Coulter, 2013) where changes in NRSF levels are moderate.

These findings support a role of NRSF in mature brain that is distinct from its role in development, when NRSF contributes to neuronal identity by repressing neuronal genes in non-neuronal tissues (Schoenherr and Anderson, 1995; Coulson, 2005), and specifies neuronal fate (Kuwabara et al., 2005). In that context, large changes in the expression of NRSF take place: NRSF levels plunge during neuronal differentiation (Gates et al., 2010; Ernsberger, 2012), de-repressing genes that contribute to neuronal identity (Wood et al., 2003; Belyaev et al., 2004; Abrajano et al., 2009). Remarkably, the gene set regulated by moderate changes in NRSF expression in the current study consisted of molecules which are extremely important for neuronal function and plasticity not only during development (Gates et al., 2010; Juliandi et al., 2010; Rodenas-Ruano et al., 2012; Pernhorst et al., 2013), but also in the adult brain (Lepagnol-Bestel et al., 2009; Gao et al., 2011; Pernhorst et al., 2011).

In summary, insult-induced increases of NRSF levels and activity contribute to epileptogenesis via NRSF-mediated repression of a group of genes that critically influence neuronal function. Of the hundreds of NRSE-containing hippocampal genes only a subset are repressed by the transcription factor in the context of seizure-induced epilepsy as evident from their rescue when the function of NRSF is blocked. The basis of the selective regulation of a subset of NRSE-containing genes includes their mid-range binding frequencies to NRSF, so that moderate fluctuations in NRSF levels influence the degree of their binding. These findings inform us about the mechanisms of neuroplasticity in the mature hippocampus.

All experiments were performed according to NIH guidelines and approved by the UCI Institutional Animal Care and Use Committee.

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Author details

1. Shawn McClelland

   1. Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, United States
   2. Department of Pediatrics, University of California, Irvine, Irvine, United States
   3. Department of Neurology, University of California, Irvine, Irvine, United States

   Contribution

   SMC, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Gary P Brennan

   Competing interests

   The authors declare that no competing interests exist.

2. Gary P Brennan

   1. Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, United States
   2. Department of Pediatrics, University of California, Irvine, Irvine, United States
   3. Department of Neurology, University of California, Irvine, Irvine, United States

   Contribution

   GPB, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Shawn McClelland

   Competing interests

   The authors declare that no competing interests exist.

3. Celine Dubé

   1. Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, United States
   2. Department of Pediatrics, University of California, Irvine, Irvine, United States
   3. Department of Neurology, University of California, Irvine, Irvine, United States

   Contribution

   CD, Conception and design, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

4. Seeta Rajpara

   1. Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, United States
   2. Department of Pediatrics, University of California, Irvine, Irvine, United States
   3. Department of Neurology, University of California, Irvine, Irvine, United States

   Contribution

   SR, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

5. Shruti Iyer

   1. Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, United States
   2. Department of Pediatrics, University of California, Irvine, Irvine, United States
   3. Department of Neurology, University of California, Irvine, Irvine, United States

   Contribution

   SI, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

6. Cristina Richichi

   1. Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, United States
   2. Department of Pediatrics, University of California, Irvine, Irvine, United States
   3. Department of Neurology, University of California, Irvine, Irvine, United States

   Contribution

   CR, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

7. Christophe Bernard

   Laboratoire Epilepsie et Cognition, Institut National de la Santé et de la Recherche Médicale, Marseille, France

   Contribution

   CB, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

8. Tallie Z Baram

   1. Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, United States
   2. Department of Pediatrics, University of California, Irvine, Irvine, United States
   3. Department of Neurology, University of California, Irvine, Irvine, United States

   Contribution

   TZB, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   tallie@uci.edu

   Competing interests

   The authors declare that no competing interests exist.

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