Abstract

Epilepsy is associated with many transcriptomic alterations. In recent years, considerable progress has been made in the identification of epilepsy-associated genes, but we have only begun to understand the underlying mechanisms of epilepsy-driven transcriptional dysregulation. This chapter reviews the state of the current knowledge regarding the transcriptional mechanisms in experimental and human epilepsy and focuses on transcription factor–mediated dysregulation. The chapter describes how the expression of epilepsy-associated genes is affected, and it discusses the possible functional consequences of these alterations in the different phases of epileptogenesis.

Introduction

Over the past several decades, the discovery of epilepsy-associated genes has increased rapidly, with almost 1,000 known epilepsy-related genes identified to date (Wang et al., 2017). Despite these developments, the underlying mechanisms that orchestrate seizure activity are still not fully understood. Current pharmacological strategies using antiepileptic drugs (AEDs) are unsuccessful at controlling seizures in up to 30% of individuals (Younus and Reddy, 2018). This pervasive pharmacoresistance, combined with the often severe side effects and sometimes even adverse effects of AEDs, pleads for a better understanding of the underlying mechanisms in order to develop more effective mechanism-based therapies.

The development of epileptic activity is etiologically complex but mostly characterized by comprehensive changes in gene expression caused by genetic variations or nongenetic factors (acquired epilepsies). Acquired epilepsies, including mesial temporal lobe epilepsy (mTLE), one of the most commonly occurring forms of epilepsy, often results from serious brain insults such as traumatic brain injury (TBI), stroke, status epilepticus (SE), and nervous system infections (Klein et al., 2018). These pathogenic insults trigger a series of molecular and cellular events over an undefined period, which eventually culminate in the emergence of spontaneous recurrent seizures. This epileptogenic period is characterized by apoptotic and necrotic cell death, chronic neuroinflammation, structural changes, synaptic reorganization, and aberrant neurogenesis (Pitkänen and Lukasiuk, 2011; Pitkänen and Engel, 2014). Underlying many, if not all, of these pathomechanisms are large-scale changes in gene expression and gene expression regulation. This can be detected at several regulatory levels of gene expression, including changes in transcription factor (TF) function, epigenetic modifications, and posttranscriptional regulators such as microRNAs and long noncoding RNAs (lncRNAs) (Henshall and Kobow, 2015; Brennan and Henshall, 2020).

TFs represent the fundamental controlling unit of transcription of genes to RNA molecules. They can activate or silence genes and often provide signaling cues to other gene expression regulatory mechanisms. Classically, TFs contain at least one DNA-binding domain (DBD), which can bind to TF-binding site (TFBS) consensus sequences usually found in promoter or enhancer regions of target genes. Importantly, many TFBSs can be found within an individual gene, and it is highly exceptional that one gene is regulated by only one specific TF.

To better understand how genes are switched “on” and “off” upon seizure induction, here we attempt to provide an overview of the transcriptional mechanisms in experimental and human epilepsy. In this chapter, we focus on the transcriptional control exerted directly by TFs; for a detailed overview of the epigenetic control mechanisms as well as the regulation by ncRNAs, we refer to Chapters 35 and 37, in this volume. Out of necessity, we will focus on a subset of transcriptional pathways and TFs, but throughout our overview, we will discuss to what extent these genes represent general pathogenic mechanisms in epilepsy. We describe how the expression of epilepsy-associated genes can be affected in experimental and human epilepsy and discuss the role of these genes in the early and chronic stages of epilepsy progression.

Transcriptional Control by FOS and JUN

Experimentally evoked and spontaneous seizures induce a rapid and transient activation of a set of genes known as immediate early genes (IEGs). These encompass several TFs, including the FOS (cFOS, FOSB, and the FOSB splice variants FOSB2 and ΔFOSB) and JUN proto-oncogenes (cJUN, JUNB, and JUND). FOS proteins heterodimerize with JUN family members to form an activator protein-1 (AP1) complex which can bind to 12-O-tetradecanoylphorbol-13-acetate (TPA)-responsive elements located in the promoter and/or enhancer regions of target genes. Importantly, the AP1 dimer can activate an auto-regulatory loop (Gazon et al., 2018) whereby further transcription of JUN and FOS genes is promoted (Fig. 34–1).

Figure 34–1.

Transcriptional feedback loops in epilepsy pathogenesis. A. Auto-regulatory feedback loop of the AP1 complex. The AP1 dimer, consisting of Fos and Jun family members, can bind to TPA-responsive elements (TREs) and activate the corresponding gene, including (more...)

Measurement of FOS and JUN expression has become a reliable marker of neuronal hyperactivity. Early studies in kindling models of epilepsy identified a rapid and robust upregulation of cFos mRNA and protein levels (Shin et al., 1990; Simonato et al., 1991). This finding has been replicated in almost all commonly used epilepsy and acute seizure models (Snyder-Keller and Pierson, 1992; Ebert and Löscher, 1995). In addition, deletion of cFos was found to attenuate kindling and kindling-induced mossy fiber sprouting, suggesting that seizure-induced activation of cFos is directly involved in the establishment of epileptic networks (Watanabe et al., 1996). Additionally, in the pilocarpine-SE model, reducing cFos levels via microRNA-mediated inhibition (miR-101a-3p) ameliorated SE-induced apoptosis, reduced autophagy levels, and promoted cell viability (Geng et al., 2021).

Also, ΔFOSB, a truncated splice variant of FOSB, has been implicated in epilepsy. ΔFosB levels are rapidly elevated in the hippocampal hilar region following pilocarpine-induced SE (You et al., 2017). Here, ΔFosB binds to the promoter of calbindin and epigenetically represses its expression. As calbindin is involved in synaptic transmission, plasticity, and cognition, suppression of calbindin by ΔFosB was hypothesized as a key regulatory mechanism in seizure induction (Emmanuele et al., 2012). Inhibition of ΔFosB in mice rescued calbindin levels and improved memory function. This indicates that ΔFosB, through regulation of calbindin and likely other genes, contributes to the persistent memory impairment and reduced cognitive function associated with TLE (You et al., 2017). Interestingly, levels of ΔFOSB were also found to be elevated in resected human tissue obtained from individuals with TLE (You et al., 2017).

Expression of JUN and the formation of the AP1 dimer are rapidly induced following epilepsy-inciting brain insults and have been shown to be influenced by etiology and age (Simonato et al., 1991; Sankar et al., 2000). cJUN activation, as well as cJUN amino-terminal kinase (JNK) signaling, is a critical mediator of cell death pathways, and activation of cJUN following epileptogenic insults is thought to initiate apoptotic signaling cascades (Schauwecker, 2000). Indeed, inhibition of JNK signaling and subsequent blockage of cJun has been shown to reduce seizure frequency (Tai et al., 2017). Unfortunately, to date, little is known about the target genes regulated by the JUN/FOS complex during epileptogenesis. Further elucidation of the role of these IEGs in epileptogenesis and the identification of their target genes would be valuable for the development of new therapeutic approaches.

Transcriptional Control by Early Growth Response Genes

Another group of IEGs involved in epilepsy-induced transcriptional dysregulation are the early growth response (EGR) proteins, a class of zinc-finger TFs composed of EGR1-4. EGR proteins are transcriptionally activated or upregulated in various animal models of epilepsy, as well as in resected cortical tissue from individuals with TLE (Honkaniemi, 1999; Rakhade et al., 2005). In addition, in individuals with TLE, subdural recordings prior to surgery showed a strong correlation between interictal spiking and activation of several IEGs, including EGR1 and EGR2 (Rakhade et al., 2005). Upon activation, EGR1 has been shown to regulate neuronal dynamics via modulation of ion channel component genes, including the transcriptional regulation of CACNA1H (encoding the T-type calcium channel Ca_V3.2) and CACNA2D4 (encoding the α2δ4 calcium channel subunit) (Van Loo et al., 2012, 2019). Interestingly, expression of both target genes was significantly increased early after pilocarpine-induced SE, and Egr1 augmentation preceded the increase of Cacna1h and Cacna2d4 (Becker et al., 2008; Van Loo et al., 2019). Elevated α2δ4 levels in hippocampal CA1 neurons seen following epileptogenic insults may disrupt CA1 neuron participation in network rhythmicity and thus increase vulnerability of the hippocampus to seizure activity (Van Loo et al., 2019).

Besides augmented Egr1 expression levels, Egr3 levels are also elevated in the hippocampus after experimentally evoked seizures (Roberts et al., 2005; López-López et al., 2017). Activation of Egr3 during epileptogenesis is associated with perturbed expression of target genes, including GABA receptor subunits and components of the NMDA receptor (Roberts et al., 2005; Kim et al., 2012).

Transcriptional Control by Serum Response Factor

The gene encoding EGR1 contains several serum response elements (SREs) which can be bound by serum response factor (SRF), another IEG. In addition, the expression levels of FOS family members can also be regulated by SRF (Vialou et al., 2010, 2012). SRF levels are rapidly and persistently elevated by epileptogenic insults (Morris et al., 1999). Interestingly, ablation of SRF blocked SE-induced Egr1 upregulation and showed reduced SE induction in the pilocarpine-SE model (Lösing et al., 2017). In addition, Srf knockout (KO) mice develop more severe and more frequent seizures following kainic acid (KA)-induced SE than their wildtype counterparts, suggesting a nuanced role for SRF in epilepsy development via regulation of both pro- and antiepileptogenic pathways (Kuzniewska et al., 2016; Lösing et al., 2017). Nevertheless, the underlying cellular mechanisms for this dual role have yet to be elucidated.

SRF also regulates the expression of the IEG neuronal Per Arnt Sim (PAS) domain protein 4 (NPAS4) (Lösing et al., 2017; Fu et al., 2020). NPAS4 is enriched in neurons and regulates the excitatory-inhibitory balance within neural circuits. NPAS4 function is required for contextual memory formation in the hippocampus and is also involved in structural and functional plasticity (Maya-Vetencourt, 2013). The expression of NPAS4 can be rapidly elevated following Ca²⁺ influx through voltage-gated channels (Bloodgood et al., 2013; Sabatini et al., 2018) where it contributes to the neuronal response via direct regulation of gene networks. Pilocarpine and other epilepsy models have shown rapid induction of Npas4 signaling following SE (Wang et al., 2014; Fu et al., 2020). The levels of NPAS4 remain elevated during the early phases of epileptogenesis and decline upon epilepsy establishment (Wang et al., 2014). Evidence suggests that NPAS4 activation may initiate neuroprotective gene expression networks which limit excitotoxicity and seizure-induced neuronal death. One of the downstream target genes of NPAS4 is synaptotagmin10 (SYT10), a membrane trafficking protein which acts as a Ca²⁺ sensor. SYT10 ablation reduces neuronal survival in response to excitotoxic stimulation, suggesting that NPAS4-mediated neuroprotection may involve regulation of membrane trafficking and fusion proteins which are essential for neuronal integrity and function (Woitecki et al., 2016). Further research is required to delineate the exact function and target genes of NPAS4 during epileptogenesis and its role in seizure-induced cell death.

Transcriptional Control by the CREB Signaling Pathway

CREB (cAMP response element-binding protein) is a stimulus-induced broad effector TF which specifically binds cAMP response elements (CREs) to regulate gene transcription. It is activated via serine phosphorylation upon which it forms homo- and heterodimers with CREB family members, including CREM (cAMP response element modulator) and ATF1 (activating transcription factor 1) (Lonze and Ginty, 2002). CREB is rapidly activated by epilepsy-inciting events such as SE and regulates gene expression patterns and subsequent neuronal excitability in distinct cortical and hippocampal cell populations (Herdegen et al., 1993; Rakhade et al., 2005). Indeed, persistent overactivation of CREB in transgenic mice leads to altered CA1 pyramidal neuron firing properties, spontaneous seizures, and excitotoxic cell death, demonstrating the potential of CREB as a critical regulator of neuronal activity (De Armentia et al., 2007). Conversely, it was observed that inhibition of CREB ameliorated SE-induced epilepsy (Zhu et al., 2012; Conte et al., 2020). Increased CREB activation has been observed in several rodent models of epileptogenesis and resected tissue from individuals with TLE (Steiger et al., 2004; Dachet et al., 2015). Pro-excitatory gene regulation by CREB is thought to be mediated, in part, by upregulation of CREB-related genes, including the inducible cAMP early repressor (ICER), an endogenous repressor of CRE-mediated transcription. The γ-form of ICER can block phospho-CREB (pCREB)-mediated gene transcription and does so at the functional CRE site within the GABRA1 gene promoter, hereby reducing the production of inhibitory receptor subunits and promoting pro-excitatory signaling pathways (Lund et al., 2008).

In addition to the transcriptional regulation of GABA receptor subunits, pCREB may also regulate cellular excitability via alternative mechanisms. CREB activation has been proposed to occur in a double-wave pattern with an initial transient wave of neuronal activation followed by a persistent activation in glial cells. Using a mouse model of impaired CREB activation, Lee and colleagues found that following pilocarpine-induced SE, levels of the pro-inflammatory enzyme cyclooxygenase-2 (Cox2) were attenuated (Lee et al., 2007). Further experiments, however, are required to understand the detailed CREB-associated gene networks and its contribution to regulating inflammatory signaling in epilepsy development.

Transcriptional Control Mechanisms by SP1

The Specificity Protein 1 (SP1) is a zinc finger TF which can bind GC-rich promoters to induce gene transcription. SP1 has been shown to regulate expression of important ion channels (e.g., KCNQ channels; Mucha et al., 2010), the epilepsy-associated adenosine kinase (ADK) gene (Kiese et al., 2016), and the epilepsy-associated synapsin 1 (SYN1) gene (Paonessa et al., 2013). SP1 is rapidly and persistently elevated in several rodent models of epileptogenesis (Feng et al., 1999; Engel et al., 2017) and initiates differential transcription of SP1 targets, including the purinergic P2X receptor 7 (P2X7R) and microRNA-22, both key regulators of neuronal activity as well as inflammatory processes (Engel et al., 2017). While a transient increase in P2X7R signaling is likely protective, triggering microglial activation and adaptive Il-1β signaling, persistent P2X7R activation, driven by SP1 dysfunction, is potentially pro-epileptogenic. Indeed, P2X7R-inhibition reduces seizure burden in epileptic mice (Jimenez-Pacheco et al., 2016). Additionally, following SE, SP1 undergoes extensive phosphorylation in astrocytes, an important site of Il-1β production during epileptogenesis (Dubé et al., 2010), further implicating SP1 as an important regulator of epilepsy-induced neuroinflammation.

Inflammation-Associated Transcriptional Regulation by NF-kB

Nuclear factor kappa B (NF-kB) is an inflammation-associated TF that resides in the cytoplasm in an inactive form where it consists of three subunits; a TF dimer; and an inhibitory subunit called IkB (inhibitor of kB). The TF dimer consists of different combinations of DNA-binding subunits, including p65 (RelA), RelB, cRel, p50, and p52 (Dresselhaus and Meffert, 2019). In neurons, the most common dimer pairing is p65 and p50. The dimer is released upon phosphorylation of the inhibitory subunit and translocates to the nucleus, where it functions as a TF. NF-kB can bind to specific DNA sequences (kB sites) within enhancer regions of genes and together with adjacent enhancer elements modulates the expression of the downstream gene, including the IkB gene, resulting in an auto-regulatory negative feedback loop (Fig. 34–1).

Activation of NF-kB can be triggered by several signaling events but is most frequently activated by tumor necrosis factor-α (TNFα), neurotrophic factors, cell adhesion molecules, and glutamate and calcium signaling (Dresselhaus and Meffert, 2019). In epilepsy, NF-kB is thought to be a critical regulator of inflammation, cell survival/death, and synaptic plasticity. NF-kB is rapidly and persistently activated in both neurons and glial cells in epileptic rodents and human TLE (Rong and Baudry, 1996; Won et al., 1999; Teocchi et al., 2013), and it is known to regulate hundreds of genes. Nevertheless, the full repertoire of genes regulated in epilepsy by NF-kB remains to be fully elucidated.

Targeting NF-kB with kB-oligonucleotides has been shown to effectively sponge NF-kB and block, at least in part, NF-kB-mediated gene networks during epileptogenesis. This resulted in a blunted inflammatory response characterized by reduced downstream inflammatory signaling molecules, including Cox2, which ameliorated epilepsy development in rodents (Di et al., 2011). The timing of NF-kB inhibition remains an important consideration, as early NF-kB activation is likely required for initial protective immune responses as well as expression of pro-survival genes.

The JAK/STAT Signaling Cascade

The JAK/STAT signaling pathway is a critical pathway for integrating external stimuli and regulating cellular responses by modifying gene expression patterns. It consists of three key components: Janus kinase (JAK), signal transducer and activator of transcription (STAT), and receptors which detect the initial stimulus (Rawlings, Rosler, and Harrison, 2004). The initial stimulus leads to activation of the JAK protein, which then recruits and activates STAT. Phosphorylated STAT forms homodimers and translocates to the nucleus, where they function as transcriptional activators, regulating genes involved in immunity and inflammation, cell survival, and neuronal activity (Harrison, 2012). Recently, however, JAKs have been shown to act independently of STATs to regulate gene expression patterns. Furthermore, STATs may dimerize and translocate to the nucleus regardless of their phosphorylation state and regulate transcription (Braunstein et al., 2003). This suggests a more complex, context-driven regulatory mechanism which has yet to be fully understood. This noncanonical transcriptional mechanism was shown to regulate the expression of many epileptogenesis-associated genes, including those involved in synaptic plasticity, inflammation, neurogenesis, and proliferation (Hixson et al., 2019).

In epilepsy models, the Jak/Stat pathway has been shown to be activated by brain-derived neurotrophic factor (Bdnf) signaling, although recent studies suggest that it may also be regulated in part by lncRNAs and microRNAs (Feng et al., 2019; Wang et al., 2020). One major contribution of Jak/Stat signaling toward establishing hyperexcitable networks is modulation of the transcriptional repressor ICER. Indeed, activation of Jak/Stat by Bdnf then results in transcriptional upregulation of ICER, which in turn reduces Gabra1 gene readout, contributing to the excitation/inhibition imbalance in epilepsy. When Jak/Stat inhibitors were employed after SE, they prevented ICER expression, restored Gabra1 levels (Lund et al., 2008), and inhibited development of spontaneous seizures in the pilocarpine-SE model (Grabenstatter et al., 2014). Activation of the Jak/Stat pathway has been shown in several chemoconvulsant rodent models, as well as following hyperthermic seizures and TBI models, suggesting that this pathway is robustly associated with epileptogenesis regardless of its etiology (Raible et al., 2015; Azevedo et al., 2018).

Zn²⁺-Induced Transcriptional Control

Some TFs control the expression of genes in a signal-specific manner. Based on this phenomenon, a new epilepsy-associated transcriptional control mechanism was recently identified, relying on the Zn²⁺-dependent transcriptional activator metal-regulatory transcription factor 1 (MTF1). Normally, Zn²⁺ levels within the cell are perfectly balanced, as Zn²⁺ becomes toxic when accumulated at high levels (Bitanihirwe and Cunningham, 2009). Under pathological conditions, such as ischemia, seizures, and brain trauma, intracellular free Zn²⁺ concentrations ([Zn²⁺]_i) can be greatly increased (Assaf and Chung, 1984; Suh, Thompson, and Frederickson, 2001). Free Zn²⁺ can bind to MTF1, usually resident within the cytoplasm. Upon Zn²⁺ binding and phosphorylation, MTF1 translocates to the nucleus, where it can bind to metal-responsive elements (MREs) in target promoters and activate expression of the corresponding genes (Andrews, 2001). To date, several genes have been described to be regulated by MTF1 in a [Zn²⁺]_i-dependent manner, including the metal ion storage metallothionein proteins (MTs) (Stuart, Searle, and Palmiter, 1985; Searle, 1990). MTs themselves have a high affinity for Zn²⁺ and act in a negative feedback loop to reduce the excess of free Zn²⁺ after epileptogenic brain insults (Fig. 34–1; Heuchel et al., 1994). Another gene regulated by MTF1 in a Zn²⁺-dependent manner is CACNA1H. In the pilocarpine-SE animal model, a temporally correlated increase in [Zn²⁺]_i, Mtf1, and Cacna1h was observed in hippocampal CA1 within the first days after SE. Interestingly, repressing this “Zn²⁺-Mtf1” signaling cascade by overexpression of a dominant-negative variant of Mtf1 in hippocampal CA1 significantly reduced the SE-induced increase in Cacna1h expression during early epileptogenesis and significantly reduced the number of seizures in the chronic stage. This model was further supported by the finding that the mRNA expression levels of MTF1 and CACNA1H in hippocampal biopsies from pharmacoresistant TLE patients strongly correlate (Van Loo et al., 2015). Recently, chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) using an antibody against MTF1 revealed enriched binding of MTF1 to the MRE consensus sequences of many other gene promoters (Tavera-Montañez et al., 2019). It, however, remains to be elucidated which additional epilepsy-associated genes are regulated by MTF1 in an ion-dependent manner. These findings nevertheless suggest that targeting the “Zn²⁺-MTF1” signaling cascade could be an intriguing strategy to pharmacologically treat pharmacoresistant TLE.

Circadian Clock-Controlled Transcription

Another pathway with transcriptional feedback loops is the circadian clock transcriptional machinery. Various epilepsies present seizures in a circadian pattern (Khan et al., 2018). Here, a variety of clock-controlled genes and TFs can disrupt sleep-wake rhythms and the circadian distribution of seizures. The two main circadian genes, also known as the core of the circadian machinery, are CLOCK (Circadian Locomotor Output Cycles Kaput) and BMAL1 (also known as ARNTL; aryl hydrocarbon receptor nuclear translocator like). Together, CLOCK and BMAL1 can form a heterodimer complex that can activate the transcription of many other genes (including the Period [PER1, PER2, and PER3], Cryptochrome [CRY1 and CRY2], REV-ERB [also known as NR1D; nuclear receptor subfamily 1 group D], and ROR [RAR-related orphan receptor] genes, as well as the PAR bZip [proline and acidic amino acid-rich basic leucine zipper] TFs DBP [D-site-binding protein], TEF [thyrotrophic embryonic factor], HLF [hepatic leukemia factor], and E4BP4 [E4 Promoter-Binding Protein 4]). In this way, the heterodimer complex of CLOCK/BMAL1 can create several transcriptional feedback loops to regulate circadian activity and seizure activity (see Fig. 34–1 for a detailed overview of the circadian clock transcriptional machinery; Gaucher, Montellier, and Sassone-Corsi, 2018; Chan and Liu, 2021).

Although our understanding of the detailed cellular and molecular mechanisms of the circadian control mechanisms regulating seizures is still incomplete, emerging studies in animal models as well as human epilepsy have revealed clear implications for the above-mentioned circadian-controlling genes in epilepsy pathogenesis. For example, Bmal1 KO mice have a reduced seizure threshold (Gerstner et al., 2014) and triple KO mice for the three PAR bZIP TFs Dbp, Tef, and Hlf developed generalized epileptic seizures (Gachon et al., 2004). Also in the KA-mouse model of TLE, injection of KA in the dorsal hippocampus resulted in altered expression of the PAR bZIP TFs (Rambousek et al., 2020). Here, the three activators Dbp, Tef, and Hlf were significantly downregulated, whereas the expression of the transcriptional repressor E4bp4 was significantly increased. These data were further supported by other genome-wide expression studies, profiling the hippocampal gene expression in acquired epilepsy animal models (Rambousek et al., 2020). In addition, the expression of other main circadian transcripts (Bmal1, Per1, Per2, Per3, Cry1, and Cry2) were also temporally altered after SE-induced epileptogenesis (Matos et al., 2018) and in human epileptogenic tissue obtained from therapeutic resections from focal epilepsy patients, a decreased CLOCK expression was observed when compared with surgical control tissue without epileptiform activity (Li et al., 2017). Furthermore, several other TFs and signaling pathways regulating the circadian clock (e.g., the mechanistic target of rapamycin [mTOR] signaling pathway and EGR1) have been implicated in the circadian pattern of seizures (Cho, 2012; Liu et al., 2018; Riedel et al., 2018). All these data clearly indicate a role for the circadian transcriptional machinery in regulating seizure activity.

NRF2-Mediated Control of Antioxidant Defenses

Nuclear factor erythroid 2-related factor 2 (NRF2) is a TF encoded by the NFE2L2 (nuclear factor, erythroid derived 2, like 2) gene in humans. It is a Cap’n’Collar basic leucine zipper (bZIP) TF, which broadly regulates and initiates transcription of a diverse set of genes involved in antioxidant responses, neuroinflammation, and antiapoptotic signaling pathways. It has been implicated in a wide range of diseases, and several NRF2 targeting compounds have been identified to promote NRF2 activity. Activation of the NRF2 enzyme has neuroprotective effects in several neurological conditions (Esteras, Dinkova-Kostova, and Abramov, 2016) and thus became a promising therapeutic candidate for epilepsy treatment due to the widespread dysregulation of antioxidant response pathways and mitochondrial disruption which characterizes the disease.

Initial reports identified that NRF2 expression is elevated in human TLE and following epileptogenic insults in preclinical models of epilepsy (Mazzuferi et al., 2013; Ruíz-Díaz et al., 2019). Indeed, analysis of differentially expressed genes in epilepsy using existing gene expression datasets identified NRF2 targets as a highly enriched set of genes accounting for 3.5% of all differentially expressed genes. Several studies have now explored the therapeutic potential of targeting NRF2 using both genetic and pharmacological approaches. Mice injected with Nrf2-containing adeno-associated viruses (AAVs) had significantly fewer generalized seizures and increased microglial quiescence compared to non-overexpressing mice (Mazzuferi et al., 2013). Recently, administration of the drug RTA408 to mice to inhibit Keap1 (Kelch ECH associating protein 1), an endogenous inhibitor of Nrf2, significantly reduced SE-induced neuronal death. Interestingly, mice treated with RTA408 developed significantly fewer spontaneous seizures over a 12-week recording period potentially via restitution of glutathione and ATP levels (Shekh-Ahmad et al., 2018). Additional information on other Nrf2 activators is reported by Patel and Walker (Chapter 31, this volume).

Transcriptional Repression by RE1-Silencing Transcription Factor

Probably the most studied transcriptional repressor in epilepsy research is the neuron restrictive silencer factor (NRSF; also known as RE1-silencing transcription factor [REST]). NRSF regulates the expression of neuronal genes involved in neuronal differentiation (Naruse et al., 1999; Paquette, Perez, and Anderson, 2000). Expressed at low levels in the adult brain, it gradually increases with age and is critical for healthy ageing, repressing genes involved in neuronal death, thereby maintaining neuronal integrity (Lu et al., 2014). NRSF is abundantly expressed in non–central nervous tissue, where it helps to maintain cell-type-specific gene expression patterns by silencing neuronal genes. NRSF establishes repressive chromatin states by binding to a canonical binding sequence called a neuron restrictive silencing element (NRSE)/repressor element 1 (RE1) (Johnson et al., 2007). Upon binding, NRSF recruits a host of co-factors, including G9a, mSin3, and methyl-CpG binding protein 2 (MeCP2), which modify the surrounding chromatin resulting in heterochromatin formation and gene silencing (Lunyak et al., 2002).

NRSF is rapidly and persistently elevated in the hippocampus following SE in rodents (Garriga-Canut et al., 2006; McClelland et al., 2011), where it establishes and maintains hyperexcitable states by binding and silencing a number of key neuronal genes, including those encoding the hyperpolarization-activated cyclic nucleotide gated channel (Hcn1), the glutamate ionotropic receptor NMDA type subunit 2A (Grin2a), the potassium voltage-gated channel subfamily C member 2 (Kcnc2), and the glycine receptor alpha 2 (Glra2), as well as several TFs and genes associated with calcium-mediated cellular processes (McClelland et al., 2014). Recently, NRSF levels were also found to be elevated in human TLE (Navarrete-Modesto et al., 2019). Inhibition of NRSF during epileptogenesis blocks NRSF-mediated gene repression and significantly ameliorates epilepsy development (McClelland et al., 2011, 2014). In addition, inhibiting NRSF levels was recently found to increase seizure threshold (Carminati et al., 2020). NRSF may also regulate processes associated with epilepsy-related comorbidities, including persistent memory impairment (Pattjerson et al., 2017). Febrile status epilepticus (FSE) is associated with an increased risk of epilepsy development in later life and can result in persistent memory impairment in some children independent of epilepsy development. Following FSE, NRSF mediates structural and functional hippocampal defects which contribute to FSE-evoked cognitive impairment. Indeed, blocking NRSF function following FSE using a single injection of NRSF-decoy oligonucleotides prevented hilar basal dendrite retention by granular cells of the dentate gyrus and improved cognitive outcomes and memory (Patterson et al., 2017).

Recently, the mechanisms governing NRSF levels in brain and during epileptogenesis were identified. Metabolically demanding brain insults like SE promote a transient increase in the NAD⁺-dependent histone deacetylase enzyme SIRT1 (Hall et al., 2017). Activated SIRT1 levels remove acetyl groups from H4K16 surrounding the microRNA-124-1 gene, which results in repression and a drop in miR-124 levels (Brennan et al., 2016). Mir-124 is an important neuronal cell fate determinant and is critical for maintenance of neuronal gene expression profiles (Åkerblom et al., 2012; Brennan et al., 2016). Reduced miR-124 results in an increase in miR-124 targets, including the CCAAT enhancer-binding protein alpha (CEBP/α), which then binds the promoter of the NRSF gene and increases transcriptional output (Åkerblom et al., 2012). NRSF levels have been shown to be influenced by cellular metabolism and metabolism-altering drugs. For example, Nrsf levels were modulated following 2-Deoxy-D-glucose administration (2-DG) in a rat kindling model. Here, 2-DG elevated NRSF levels resulted in reduced Bdnf-TrkB signaling, which had anticonvulsant and antiepileptic effects (Garriga-Canut et al., 2006). Combined, these data demonstrate that identification of the mechanisms governing TF regulation may be important in developing targeted therapeutic options for the treatment of acquired epilepsy.

Genetic Variants and Transcriptional Control Mechanisms

As described above, differences in gene expression of key TFs are a primary cause of transcriptional dysregulation in epilepsy pathogenesis. However, genetic variants may alter transcriptional efficacy, conferring an additional layer of transcriptional complexity controlling neuronal function. Recently, our understanding of the genetic risk variants for epilepsy has increased enormously due to the immense progress in deep sequencing approaches. To date, most genetic alterations identified in genetic epilepsies are located within the coding region of a gene. However, this bias is potentially skewed, as currently most sequencing-based studies in epilepsy research are primarily limited to the protein-coding region of the genome, meaning risk variants outside the exome are underrepresented. Such noncoding variants, however, can reside in essential elements of the genome, including the promoter region, a cis- or trans-regulatory region (e.g., enhancer or repressor elements), or a splice site of the gene.

How can noncoding genetic variants influence the transcriptional machinery in epilepsy pathogenesis? If the genetic variant is located within the promoter region of the causative/susceptibility gene, a TFBS might be disrupted or created, leading to affected TF binding, and thus altered expression of the corresponding gene. For example, disrupted SP1 binding was observed in several promoters of genes associated with epilepsy, including in the cystatin B (CSTB) promoter (Alakurtti et al., 2000) and the potassium channel Kv8.1 (KCNV1) gene (Ebihara et al., 2004). In addition, in childhood absence epilepsy (CAE), a promoter haplotype consisting of 13 SNPs in the GABRB3 gene impaired binding of the neuron-specific transcriptional activator N-Oct-3 (Urak et al., 2006), and in Dravet syndrome, a genetic variant within the promoter region of arachidonate lipoxygenase 3 (ALOXE3; c.-50C > G) resulted in altered binding of the TF NFII-I (Gao et al., 2021). For both promoter variations, reporter gene assays revealed that the disease-associated variants induced a significantly lower transcriptional activity than the control variants. Also, in acquired epilepsies, noncoding genetic variants may play a role in seizure susceptibility. In TLE, two linked single-nucleotide polymorphisms (SNPs) located in the promoter region of aldehyde dehydrogenase 5a1 (succinic semialdehyde dehydrogenase; ALDH5A1) associated with altered ALDH5A1 mRNA expression in epileptic hippocampi. Here, the minor ALDH5A1-GG haplotype associated with reduced ALDH5A1 expression levels and was thought to be caused by reduced binding of EGR1 (Tsortouktzidis et al., 2021). To date, many other noncoding potentially functional variants have been linked with epilepsy pathogenesis, including variants in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene (Nakayama et al., 2010; Gao et al., 2017; de Lange et al., 2019), corticotropin-releasing hormone gene (CRH) (Combi et al., 2005), and CSTB gene (Lafrenière et al., 1997; Virtaneva et al., 1997; Borel et al., 2012). However, the exact regulatory mechanisms by which such noncoding variants can alter gene expression are mostly still unknown.

Genetic alterations within genes encoding components of the transcriptional machinery may also cause regulatory deficits resulting in seizures. For instance, genetic variations within the chromodomain helicase DNA-binding protein 2 (CHD2) gene are associated with various epilepsy phenotypes, ranging from mild febrile seizures to severe epileptic encephalopathies (Chen et al., 2020; Wilson et al., 2021). CHD proteins are essential for shaping chromatin structure and therefore regulate the transcription of many genes, including those involved in development, cell cycle regulation, and cell differentiation (Mills, 2017). It is therefore not surprising that, to date, almost 70 unique variants within CHD2 have been described and the effect of each variant on the resultant protein may contribute to the diverse phenotypic spectrum of epilepsy associated with this condition (Chen et al., 2020).

Also many pathogenic variants within myocyte enhancer factor-2 polypeptide C (MEF2C), another component of the transcriptional machinery, are associated with a broad spectrum of epileptiform activity (Borlot et al., 2019). Here, affected transcriptional control mechanisms result in diminished expression of MECP2 and cyclin-dependent kinase like 5 (CDKL5) (Zweier et al., 2010), two genes genetically linked to two rare X-linked developmental brain disorders presenting with seizures, Rett syndrome and CDKL5 deficiency disorder, respectively (Kadam et al., 2019).

Differential Transcriptional Regulation by Alternative Promoters

Another level of transcriptional regulation is mediated by the differential usage of alternative promoters within a gene. Almost one-fifth of human genes have multiple promoters (Landry, Mager, and Wilhelm, 2003), and a large number of genes associated with a neurological disease are controlled by alternative promoter regulation (Pal et al., 2011). Also in epilepsy pathogenesis, alternative promoter usage has been described. For example, isoforms of the metabotropic GABA_B receptor 1 (GABA_BR1a and GABA_BR1b), a protein genetically linked to TLE (Kauffman et al., 2008) and important for the slow and prolonged inhibitory synaptic transmission (Bettler et al., 2004), are produced by alternative promoter regulation (Steiger et al., 2004). Also the neuronal KCl cotransporter 2 gene (KCC2; also known as SLC12A5), a gene associated with idiopathic generalized epilepsy (IGE) and crucial for chloride homeostasis in neurons and the dynamic control of GABA_A and glycine receptor functioning (Kahle et al., 2014), can generate two neuron-specific transcriptional variants by using alternative promoters (Uvarov et al., 2007). Probably the most studied gene with differential promoter usage is the BDNF gene. Although BDNF is not a TF, it can profoundly influence gene readout by modulating the activity of TFs. BDNF is a member of the neurotrophin family of growth factors and regulates a large variety of biological functions, including the survival and differentiation of various neuronal populations and the regulation of synaptic transmission and plasticity (Kowiański et al., 2018). Expression of BDNF and its associated receptor the tyrosine-related kinase B receptor (TRKB) are rapidly elevated in animal models of epilepsy and have also been shown to be persistently elevated in human TLE (Mathern et al., 1997; Danzer, He, and McNamara, 2004). In addition, genetic studies have revealed that a naturally occurring functional polymorphism within the human BDNF gene (Val66Met) is associated with fragile X syndrome (FXS) and TLE (Louhivuori et al., 2009; Shen et al., 2016).

Transcription of the BDNF gene is regulated in a highly sophisticated manner via alternative promoters, splicing events, and the use of alternative poly(A) sites (Keifer, 2021). To date, nine specific promoters have been identified in the rodent and human BDNF gene, and each individual promoter is regulated by a specific subset of TFs (Pruunsild et al., 2007; Park and Poo, 2013). The alternative promoters also have a tissue- and cell-type- specific sensitivity for distinct patterns of stimuli and may become activated under different physiological conditions. In experimental and human epilepsy, differential usage of alternative BDNF promoters has been described after KA and pilocarpine administration in rodents (Timmusk et al., 1993; Chiaruttini et al., 2008) and in hippocampi of patients with pharmacoresistant TLE (Martínez-Levy et al., 2016). In addition, genetically modified mice in which transcription of a specific Bdnf promoter was inhibited displayed clear alterations at various levels, for example, altered GABAergic transmission and cortical synaptic plasticity in mice with inhibited promoter IV-driven Bdnf expression (Sakata et al., 2009). Furthermore, in mice lacking Bdnf expression from promoters IV and VI, but not I and II, an impaired GABAergic expression in prefrontal cortex (PFC) interneurons was observed (Maynard et al., 2016). A better understanding of these highly sophisticated promoter-dependent transcriptional mechanisms may lead to improved, more-targeted therapeutic approaches, with potentially lower side effects.

Summary and Future Course

In this chapter, we summarized the transcriptional mechanisms relevant in experimental and human epilepsy (Fig. 34–2). We have observed many TFs to be affected in both animal models and in surgically resected human tissue. Nevertheless, although such similarities were found, the pathophysiological significance of the described alterations observed in experimental and human epilepsies may be very different and should be interpreted with caution.

Figure 34–2.

Epilepsy-related signaling pathways regulated by transcription factors in neurons and microglia. The schematic shows examples of changes to gene targets of epilepsy-associated transcription factors. After epilepsy-promoting insults, activation of several (more...)

To date, many pathways have been identified and clearly play an important role in the different phases of epileptogenesis. However, the detailed control mechanisms remain largely unexplored. The fact that many TFs are involved in the regulation of one gene, and different TFs might compete for one TFBS, significantly complicates our understanding of transcriptional output. In addition, a complex interplay among activating TFs and subsequent waves of repressive transcriptional elements, as seen for CACNA1H regulation (Van Loo et al., 2012, 2015), also makes the identification of defined control mechanisms more complex. Better knowledge of the detailed transcriptional control mechanisms, however, will be necessary to improve our understanding of transcriptional dysregulation in epilepsy and might illuminate new avenues for therapeutic strategies. TFs have become attractive therapeutic targets due to their intrinsic involvement in establishing and maintaining seizure activity. Several drugs already in clinical use target TFs, including Tamoxifen and bicalutamide for the treatment of breast and prostate cancer, respectively (Lambert et al., 2018). However, their usage in epilepsy treatment strategies has yet to be explored.

To get a better insight into the detailed transcriptional control mechanisms, it would be ideal to identify the key epilepsy-associated regulators, also known as “master regulators.” Such a “master regulator” is at the very top of the transcriptional cascade, controlling the expression of multiple other TFs and associated genes. It has been hypothesized that only one or two of such “master regulators” controls the expression of the other genes, resulting in a particular disease state (Sikdar and Datta, 2017). One potential candidate of a transcriptional “master regulator” in epilepsy could be the transcriptional repressor NRSF. Due to its central role, NRSF was recently postulated to function as a “master regulator” in several neurologic disorders and diseases, including epilepsy, stroke, ischemia, Alzheimer disease, and Huntington disease (Hwang and Zukin, 2018). Another potential “master regulator” is the IEG SRF, as it regulates the expression of several other epilepsy-associated IEGs, including EGR1, NPAS4, and FOS family members (Vialou et al., 2010; Lösing et al., 2017). EGR1, itself is also a viable “master regulator” candidate; more than 50% of the genes expressed in human cell lines contain an EGR1 binding site within 3 kb of their transcription start site (TSS) (Duclot and Kabbaj, 2017), and multiple epilepsy-associated genes are directly regulated by binding of EGR1 within their promoter sequences (Van Loo et al., 2012, 2019; Tsortouktzidis et al., 2021). However, although such TFs might function as “master regulators” in experimental epilepsy models, it does not guarantee direct translation to the human epilepsies.

How can we improve our understanding of the transcriptional control mechanisms in epilepsy? Most of our current knowledge comes from animal models or from expression studies of resected tissue from human epilepsy patients. However, as no single animal model of epilepsy completely represents all features of the human condition (Kandratavicius et al., 2014; Grone and Baraban, 2015), it is not surprising that differences in gene expression found in the animal model cannot always be translated to the human situation. In addition, transcriptomic profiling in human tissue has its limitations. The high heterogeneity among patients, the often-large history of treatment with antiepileptic drugs, and the lack of proper control tissue, complicates accurate transcriptomic profiling. Ideally, one would analyze one patient systematically at various levels (e.g., electroencephalographic [EEG] monitoring, intraoperative electrocorticography [ECoG] recordings, single-cell or single-nuclear RNAseq, spatial transcriptomics, and electrophysiological measurements combined with patch-seq experiments on organotypic brain slice cultures). In this way, a complete spectrum of individual-specific data will be obtained, allowing precise transcriptomic profiling in human tissue. Such individual-specific datamining constitutes a promising step toward the design of new targeted-gene approaches and precision medicine-based therapeutic interventions with lower side effects.

Acknowledgments

References

1. Åkerblom, M., Sachdeva, R., Barde, I., Verp, S., Gentner, B., Trono, D. and Jakobsson, J. (2012) ‘MicroRNA-124 is a subventricular zone neuronal fate determinant’, Journal of Neuroscience. J Neurosci, 32(26), pp. 8879–8889. doi: 10.1523/JNEUROSCI.0558-12.2012. PMID: 22745489. [PMC free article: PMC4434222] [PubMed: 22745489]
2. Alakurtti, K., Virtaneva, K., Joensuu, T., Palvimo, J. J. and Lehesjoki, A. E. (2000) ‘Characterization of the cystatin B gene promoter harboring the dodecamer repeat expanded in progressive myoclonus epilepsy,  EPM1’, Gene. Gene, 242(1–2), pp. 65–73. doi: 10.1016/S0378-1119(99)00550-8. PMID: 10721698. [PubMed: 10721698]
3. Andrews, G. K. (2001) ‘Cellular zinc sensors: MTF-1 regulation of gene expression’, BioMetals, 14(3-4), pp. 223–237. doi: 10.1023/A:1012932712483. PMID: 11831458. [PubMed: 11831458]
4. De Armentia, M. L., Jancic, D., Olivares, R., Alarcon, J. M., Kandel, E. R. and Barco, A. (2007) ‘cAMP response element-binding protein-mediated gene expression increases the intrinsic excitability of CA1 pyramidal neurons’, Journal of Neuroscience. J Neurosci, 27(50), pp. 13909–13918. doi: 10.1523/JNEUROSCI.3850-07.2007. PMID: 18077703. [PMC free article: PMC6673625] [PubMed: 18077703]
5. Assaf, S. Y. and Chung, S. H. (1984) ‘Release of endogenous Zn2+ from brain tissue during activity’, Nature. Nature, 308(5961), pp. 734–736. doi: 10.1038/308734a0. PMID: 6717566. [PubMed: 6717566]
6. Azevedo, H., Khaled, N. A., Santos, P., Bertonha, F. B. and Moreira-Filho, C. A. (2018) ‘Temporal analysis of hippocampal CA3 gene coexpression networks in a rat model of febrile seizures’, DMM Disease Models and Mechanisms. Company of Biologists Ltd, 11(1):dmm029074. doi: 10.1242/dmm.029074. PMID: 29196444. [PMC free article: PMC5818071] [PubMed: 29196444]
7. Becker, A. J., Pitsch, J., Sochivko, D., Opitz, T., Staniek, M., Chen, C.-C., Campbell, K. P., Schoch, S., Yaari, Y. and Beck, H. (2008) ‘Transcriptional Upregulation of Cav3.2 Mediates Epileptogenesis in the Pilocarpine Model of Epilepsy’, J. Neurosci., 28(49), pp. 13341–13353. doi: 10.1523/JNEUROSCI.1421-08.2008. PMID: 19052226. [PMC free article: PMC6671595] [PubMed: 19052226]
8. Bettler, B., Kaupmann, K., Mosbacher, J. and Gassmann, M. (2004) ‘Molecular structure and physiological functions of GABAB receptors’, Physiol Rev, 84(3), pp. 835–867. doi: 10.1152/physrev.00036.2003. PMID: 15269338. [PubMed: 15269338]
9. Bitanihirwe, B. K. Y. and Cunningham, M. G. (2009) ‘Zinc: The brain’s dark horse’, Synapse, 63(11), pp. 1029–1049. doi: 10.1002/syn.20683. PMID: 19623531. [PubMed: 19623531]
10. Bloodgood, B. L., Sharma, N., Browne, H. A., Trepman, A. Z. and Greenberg, M. E. (2013) ‘The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition’, Nature. Nature, 503(7474), pp. 121–125. doi: 10.1038/nature12743. PMID: 24201284. [PMC free article: PMC4169177] [PubMed: 24201284]
11. Borel, C., Migliavacca, E., Letourneau, A., Gagnebin, M., Béna, F., Sailani, M. R., Dermitzakis, E. T., Sharp, A. J. and Antonarakis, S. E. (2012) ‘Tandem repeat sequence variation as causative Cis-eQTLs for protein-coding gene expression variation: The case of CSTB’, Human Mutation. 33(8), pp. 1302-1309. doi: 10.1002/humu.22115. PMID: 22573514. [PubMed: 22573514]
12. Borlot, F., Whitney, R., Cohn, R. D. and Weiss, S. K. (2019) ‘MEF2C-related epilepsy: Delineating the phenotypic spectrum from a novel mutation and literature review’, Seizure. 67, pp. 86–90. doi: 10.1016/j.seizure.2019.03.015. PMID: 30922778. [PubMed: 30922778]
13. Braunstein, J., Brutsaert, S., Olson, R. and Schindler, C. (2003) ‘STATs Dimerize in the Absence of Phosphorylation’, Journal of Biological Chemistry. J Biol Chem, 278(36), pp. 34133–34140. doi: 10.1074/jbc.M304531200. PMID: 12832402. [PubMed: 12832402]
14. Brennan, G. P., Dey, D., Chen, Y., Patterson, K. P., Magnetta, E. J., Hall, A. M., Dube, C. M., Mei, Y. T. and Baram, T. Z. (2016) ‘Dual and Opposing Roles of MicroRNA-124 in Epilepsy Are Mediated through Inflammatory and NRSF-Dependent Gene Networks’, Cell Reports. Elsevier B.V., 14(10), pp. 2402–2412. doi: 10.1016/j.celrep.2016.02.042. PMID: 26947066. [PMC free article: PMC4794429] [PubMed: 26947066]
15. Brennan, G. P. and Henshall, D. C. (2020) ‘MicroRNAs as regulators of brain function and targets for treatment of epilepsy’, Nature Reviews Neurology. Springer US, 16(9), pp. 506–519. doi: 10.1038/s41582-020-0369-8. PMID: 32546757. [PubMed: 32546757]
16. Carminati, E., Buffolo, F., Rocchi, A., Michetti, C., Cesca, F. and Benfenati, F. (2020) ‘Mild Inactivation of RE-1 Silencing Transcription Factor (REST) Reduces Susceptibility to Kainic Acid-Induced Seizures’, Frontiers in Cellular Neuroscience. Frontiers Media S.A., 13, pp. 580. doi: 10.3389/fncel.2019.00580. PMID: 31998079. [PMC free article: PMC6965066] [PubMed: 31998079]
17. Chan, F. and Liu, J. (2021) ‘Molecular regulation of brain metabolism underlying circadian epilepsy’, Epilepsia. Blackwell Publishing Inc., 62(S1), pp. S32–S48. doi: 10.1111/epi.16796. PMID: 33395505. [PMC free article: PMC8744084] [PubMed: 33395505]
18. Chen, J., Zhang, J., Liu, A., Zhang, L., Li, H., Zeng, Q., Yang, Z., Yang, X., Wu, X. and Zhang, Y. (2020) ‘CHD2-related epilepsy: novel mutations and new phenotypes’, Developmental Medicine and Child Neurology. 62(5):647-653. doi: 10.1111/dmcn.14367. PMID: 31677157. [PubMed: 31677157]
19. Chiaruttini, C., Sonego, M., Baj, G., Simonato, M. and Tongiorgi, E. (2008) ‘BDNF mRNA splice variants display activity-dependent targeting to distinct hippocampal laminae.’, Molecular and cellular neurosciences. Mol Cell Neurosci, 37(1), pp. 11–9. doi: 10.1016/j.mcn.2007.08.011. PMID: 17919921. [PubMed: 17919921]
20. Cho, C. H. (2012) ‘Molecular mechanism of circadian rhythmicity of seizures in temporal lobe epilepsy’, Frontiers in Cellular Neuroscience. Front Cell Neurosci, 6:55. doi: 10.3389/fncel.2012.00055. PMID: 23189039. [PMC free article: PMC3504933] [PubMed: 23189039]
21. Combi, R., Dalprà, L., Ferini-Strambi, L. and Tenchini, M. L. (2005) ‘Frontal lobe epilepsy and mutations of the corticotropin-releasing hormone gene’, Annals of Neurology. doi: 10.1002/ana.20660. PMID: 16222669. [PubMed: 16222669]
22. Conte, G., Parras, A., Alves, M., Ollà, I., De Diego-Garcia, L., Beamer, E., Alalqam, R., Ocampo, A., Mendez, R., Henshall, D. C., Lucas, J. J. and Engel, T. (2020) ‘High concordance between hippocampal transcriptome of the mouse intra-amygdala kainic acid model and human temporal lobe epilepsy’, Epilepsia, 61(12), pp. 2795–2810. doi: 10.1111/epi.16714. PMID: 33070315. [PubMed: 33070315]
23. Dachet, F., Bagla, S., Keren-Aviram, G., Morton, A., Balan, K., Saadat, L., Valyi-Nagy, T., Kupsky, W., Song, F., Dratz, E. and Loeb, J. A. (2015) ‘Predicting novel histopathological microlesions in human epileptic brain through transcriptional clustering’, Brain. Oxford University Press, 138(2), pp. 356–370. doi: 10.1093/brain/awu350. PMID: 25516101. [PMC free article: PMC4306820] [PubMed: 25516101]
24. Danzer, S. C., He, X. and McNamara, J. O. (2004) ‘Ontogeny of seizure-induced increases in BDNF immunoreactivity and TrkB receptor activation in rat hippocampus’, Hippocampus. Hippocampus, 14(3), pp. 345–355. doi: 10.1002/hipo.10190. PMID: 15132434. [PubMed: 15132434]
25. Di, Q., Yu, N., Liu, H., Hu, Y., Jiang, Y., Yan, Y. K., Zhang, Y. F. and Zhang, Y. D. (2011) ‘Nuclear factor-kappa B activity regulates brain expression of P-glycoprotein in the kainic acid-induced seizure rats’, Mediators of Inflammation. Hindawi Limited, 2011. doi: 10.1155/2011/670613. PMID: 21403895. [PMC free article: PMC3043292] [PubMed: 21403895]
26. Dresselhaus, E. C. and Meffert, M. K. (2019) ‘Cellular specificity of NF-κB function in the nervous system’, Frontiers in Immunology. Frontiers Media S.A. doi: 10.3389/fimmu.2019.01043. PMID: 31143184. [PMC free article: PMC6520659] [PubMed: 31143184]
27. Dubé, C. M., Ravizza, T., Hamamura, M., Zha, Q., Keebaugh, A., Fok, K., Andres, A. L., Nalcioglu, O., Obenaus, A., Vezzani, A. and Baram, T. Z. (2010) ‘Epileptogenesis provoked by prolonged experimental febrile seizures: Mechanisms and biomarkers’, Journal of Neuroscience. J Neurosci, 30(22), pp. 7484–7494. doi: 10.1523/JNEUROSCI.0551-10.2010. PMID: 20519523. [PMC free article: PMC2906240] [PubMed: 20519523]
28. Duclot, F. and Kabbaj, M. (2017) ‘The Role of Early Growth Response 1 (EGR1) in Brain Plasticity and Neuropsychiatric Disorders’, Frontiers in Behavioral Neuroscience. Frontiers Media S.A., 11, pp. 35. doi: 10.3389/fnbeh.2017.00035. PMID: 28321184. [PMC free article: PMC5337695] [PubMed: 28321184]
29. Ebert, U. and Löscher, W. (1995) ‘Strong induction of c-fos in the piriform cortex during focal seizures evoked from different limbic brain sites’, Brain Research. Brain Res, 671(2), pp. 338–344. doi: 10.1016/0006-8993(94)01401-3. PMID: 7743227. [PubMed: 7743227]
30. Ebihara, M., Ohba, H., Kikuchi, M. and Yoshikawa, T. (2004) ‘Structural characterization and promoter analysis of human potassium channel Kv8.1 (KCNV1) gene’, Gene. Elsevier, 325(1–2), pp. 89–96. doi: 10.1016/j.gene.2003.09.044. PMID: 14697513. [PubMed: 14697513]
31. Emmanuele, V., Garcia-Cazorla, A., Huang, H. Bin, Çoku, J., Dorado, B., Cortes, E. P., Engelstad, K., De Vivo, D. C., Dimauro, S., Bonilla, E. and Tanji, K. (2012) ‘Decreased hippocampal expression of calbindin D28K and cognitive impairment in MELAS’, Journal of the Neurological Sciences. J Neurol Sci, 317(1–2), pp. 29–34. doi: 10.1016/j.jns.2012.03.005. PMID: 22483853. [PMC free article: PMC3345503] [PubMed: 22483853]
32. Engel, T., Brennan, G. P., Sanz-Rodriguez, A., Alves, M., Beamer, E., Watters, O., Henshall, D. C. and Jimenez-Mateos, E. M. (2017) ‘A calcium-sensitive feed-forward loop regulating the expression of the ATP-gated purinergic P2X7 receptor via specificity protein 1 and microRNA-22’, Biochimica et Biophysica Acta—Molecular Cell Research. Elsevier B.V., 1864(2), pp. 255–266. doi: 10.1016/j.bbamcr.2016.11.007. PMID: 27840225. [PubMed: 27840225]
33. Esteras, N., Dinkova-Kostova, A. T. and Abramov, A. Y. (2016) ‘Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function’, Biological Chemistry. Biol Chem, 397(5), pp. 383–400. doi: 10.1515/hsz-2015-0295. [PubMed: 26812787]
34. Feng, X., Xiong, W., Yuan, M., Zhan, J., Zhu, X., Wei, Z., Chen, X. and Cheng, X. (2019) ‘Down-regulated microRNA-183 mediates the Jak/Stat signaling pathway to attenuate hippocampal neuron injury in epilepsy rats by targeting Foxp1’, Cell Cycle. Taylor and Francis Inc., 18(22), pp. 3206–3222. doi: 10.1080/15384101.2019.1671717. PMID: 31571517. [PMC free article: PMC6816400] [PubMed: 31571517]
35. Feng, Z., Chang, R. C. C., Bing, G., Hudson, P., Tiao, N., Jin, L. and Hong, J. S. (1999) ‘Long-term increase of Sp-1 transcription factors in the hippocampus after kainic acid treatment’, Molecular Brain Research. Elsevier, 69(1), pp. 144–148. doi: 10.1016/S0169-328X(99)00099-6. PMID: 10350646. [PubMed: 10350646]
36. Fu, J., Guo, O., Zhen, Z. and Zhen, J. (2020) ‘Essential Functions of the Transcription Factor Npas4 in Neural Circuit Development, Plasticity, and Diseases’, Frontiers in Neuroscience, 14. doi: 10.3389/fnins.2020.603373. PMID: 33335473. [PMC free article: PMC7736240] [PubMed: 33335473]
37. Gachon, F., Fonjallaz, P., Damiola, F., Gos, P., Kodama, T., Zakany, J., Duboule, D., Petit, B., Tafti, M. and Schibler, U. (2004) ‘The loss of circadian PAR bZip transcription factors results in epilepsy’, Genes and Development. Genes Dev, 18(12), pp. 1397–1412. doi: 10.1101/gad.301404. PMID: 15175240. [PMC free article: PMC423191] [PubMed: 15175240]
38. Gao, M.-M., Huang, H.-Y., Chen, S.-Y., Tang, H.-L., He, N., Feng, W.-C., Lu, P., Hu, F., Yan, H.-J. and Long, Y.-S. (2021) ‘The ALOXE3 gene variants from patients with Dravet syndrome decrease gene expression and enzyme activity’, Brain Research Bulletin , 170, pp. 81–89. doi: 10.1016/j.brainresbull.2021.02.010. PMID: 33581311. [PubMed: 33581311]
39. Gao, Q. W., Hua, L. D., Wang, J., Fan, C. X., Deng, W. Y., Li, B., Bian, W. J., Shao, C. X., He, N., Zhou, P., Liao, W. P. and Shi, Y. W. (2017) ‘A Point Mutation in SCN1A 5′ Genomic Region Decreases the Promoter Activity and Is Associated with Mild Epilepsy and Seizure Aggravation Induced by Antiepileptic Drug’, Molecular Neurobiology, 54(4), pp. 2428–2434. doi: 10.1007/s12035-016-9800-y. PMID: 26969601. [PubMed: 26969601]
40. Garriga-Canut, M., Schoenike, B., Qazi, R., Bergendahl, K., Daley, T. J., Pfender, R. M., Morrison, J. F., Ockuly, J., Stafstrom, C., Sutula, T. and Roopra, A. (2006) ‘2-Deoxy-D-glucose reduces epilepsy progression by NRSF-CtBP-dependent metabolic regulation of chromatin structure’, Nature Neuroscience. Nat Neurosci, 9(11), pp. 1382–1387. doi: 10.1038/nn1791. PMID: 17041593. [PubMed: 17041593]
41. Gaucher, J., Montellier, E. and Sassone-Corsi, P. (2018) ‘Molecular Cogs: Interplay between Circadian Clock and Cell Cycle’, Trends in Cell Biology. Elsevier Ltd, 28(5), pp. 368–379. doi: 10.1016/j.tcb.2018.01.006. PMID: 29471986. [PubMed: 29471986]
42. Gazon, H., Barbeau, B., Mesnard, J. M. and Peloponese, J. M. (2018) ‘Hijacking of the AP-1 signaling pathway during development of ATL’, Frontiers in Microbiology.  Frontiers Media S.A, 8, pp. 2686. doi: 10.3389/fmicb.2017.02686. PMID: 29379481. [PMC free article: PMC5775265] [PubMed: 29379481]
43. Geng, Jiefeng, Zhao, H., Liu, X., Geng, Junjie, Gao, Y. and He, B. (2021) ‘MiR-101a-3p Attenuated Pilocarpine-Induced Epilepsy by Downregulating c-FOS’, Neurochemical Research.  Springer, 46(5). doi: 10.1007/s11064-021-03245-w. PMID: 33559830. [PubMed: 33559830]
44. Gerstner, J. R., Smith, G. G., Lenz, O., Perron, I. J., Buono, R. J. and Ferraro, T. N. (2014) ‘BMAL1 controls the diurnal rhythm and set point for electrical seizure threshold in mice’, Frontiers in Systems Neuroscience. Frontiers Research Foundation, 8, pp. 121. doi: 10.3389/fnsys.2014.00121. PMID: 25018707. [PMC free article: PMC4071977] [PubMed: 25018707]
45. Grabenstatter, H. L., Del Angel, Y. C., Carlsen, J., Wempe, M. F., White, A. M., Cogswell, M., Russek, S. J. and Brooks-Kayal, A. R. (2014) ‘The effect of STAT3 inhibition on status epilepticus and subsequent spontaneous seizures in the pilocarpine model of acquired epilepsy.’, Neurobiology of disease. Neurobiol Dis, 62, pp. 73–85. doi: 10.1016/j.nbd.2013.09.003. PMID: 24051278. [PMC free article: PMC3908775] [PubMed: 24051278]
46. Grone, B. P. and Baraban, S. C. (2015) ‘Animal models in epilepsy research: Legacies and new directions’, Nature Neuroscience.  Nature Publishing Group, pp. 339–343. doi: 10.1038/nn.3934. PMID: 25710835. [PubMed: 25710835]
47. Hall, A. M., Brennan, G. P., Nguyen, T. M., Singh-Taylor, A., Mun, H. S., Sargious, M. J. and Baram, T. Z. (2017) ‘The role of Sirt1 in epileptogenesis’, eNeuro. Society for Neuroscience, 4(1): ENEURO.0301-16.2017. doi: 10.1523/ENEURO.0301-16.2017. PMID: 28197553. [PMC free article: PMC5301079] [PubMed: 28197553]
48. Harrison, D. A. (2012) ‘The JAK/STAT pathway’, Cold Spring Harbor Perspectives in Biology.  Cold Spring Harb Perspect Biol, 4(3):a011205. doi: 10.1101/cshperspect.a011205. PMID: 22383755. [PMC free article: PMC3282412] [PubMed: 22383755]
49. Henshall, D. C. (2020) ‘Epigenetics and noncoding RNA: Recent developments and future therapeutic opportunities’, European Journal of Paediatric Neurology. W.B. Saunders Ltd, pp. 30–34. doi: 10.1016/j.ejpn.2019.06.002. PMID: 31235424. [PubMed: 31235424]
50. Henshall, D. C. and Kobow, K. (2015) ‘Epigenetics and epilepsy’, Cold Spring Harbor Perspectives in Medicine.  Cold Spring Harbor Laboratory Press, 5(12): a022731. doi: 10.1101/cshperspect.a022731. PMID: 26438606. [PMC free article: PMC4665035] [PubMed: 26438606]
51. Herdegen, T., Sandkühler, J., Gass, P., Kiessling, M., Bravo, R. and Zimmermann, M. (1993) ‘JUN, FOS, KROX, and CREB transcription factor proteins in the rat cortex: Basal expression and induction by spreading depression and epileptic seizures’, Journal of Comparative Neurology.  J Comp Neurol, 333(2), pp. 271–288. doi: 10.1002/cne.903330212. PMID: 8345107. [PubMed: 8345107]
52. Heuchel, R., Radtke, F., Georgiev, O., Stark, G., Aguet, M. and Schaffner, W. (1994) ‘The transcription factor MTF-1 is essential for basal and heavy metal-induced metallothionein gene expression’, EMBO Journal. Wiley-VCH Verlag, 13(12), pp. 2870–2875. doi: 10.1002/j.1460-2075.1994.tb06581.x. PMID: 8026472. [PMC free article: PMC395168] [PubMed: 8026472]
53. Hixson, K. M., Cogswell, M., Brooks-Kayal, A. R. and Russek, S. J. (2019) ‘Evidence for a non-canonical JAK/STAT signaling pathway in the synthesis of the brain’s major ion channels and neurotransmitter receptors’, BMC Genomics. BioMed Central Ltd., 20(1). doi: 10.1186/s12864-019-6033-2. PMID: 31455240. [PMC free article: PMC6712773] [PubMed: 31455240]
54. Honkaniemi, J. (1999) ‘Prolonged expression of zinc finger immediate-early gene mRNAs and decreased protein synthesis following kainic acid induced seizures’, European Journal of Neuroscience. Eur J Neurosci, 11(1), pp. 10–17. doi: 10.1046/j.1460-9568.1999.00401.x. PMID: 9987007. [PubMed: 9987007]
55. Hwang, J. Y. and Zukin, R. S. (2018) ‘REST, a master transcriptional regulator in neurodegenerative disease’, Current Opinion in Neurobiology.  Elsevier Ltd, 48, pp. 193–200. doi: 10.1016/j.conb.2017.12.008. PMID: 29351877. [PMC free article: PMC5892838] [PubMed: 29351877]
56. Jimenez-Pacheco, A., Diaz-Hernandez, M., Arribas-Blázquez, M., Sanz-Rodriguez, A., Olivos-Oré, L. A., Artalejo, A. R., Alves, M., Letavic, M., Teresa Miras-Portugal, M., Conroy, R. M., Delanty, N., Farrell, M. A., O’Brien, D. F., Bhattacharya, A., Engel, T. and Henshall, D. C. (2016) ‘Transient P2X7 receptor antagonism produces lasting reductions in spontaneous seizures and gliosis in experimental temporal lobe epilepsy’, Journal of Neuroscience. Society for Neuroscience, 36(22), pp. 5920–5932. doi: 10.1523/JNEUROSCI.4009-15.2016. PMID: 27251615. [PMC free article: PMC6601816] [PubMed: 27251615]
57. Johnson, D. S., Mortazavi, A., Myers, R. M. and Wold, B. (2007) ‘Genome-wide mapping of in vivo protein-DNA interactions’, Science. Science, 316(5830), pp. 1497–1502. doi: 10.1126/science.1141319. PMID: 17540862. [PubMed: 17540862]
58. Kadam, S. D., Sullivan, B. J., Goyal, A., Blue, M. E. and Smith-Hicks, C. (2019) ‘Rett syndrome and CDKL5 deficiency disorder: From bench to clinic’, International Journal of Molecular Sciences. MDPI AG, 20(20). doi: 10.3390/ijms20205098. PMID: 31618813. [PMC free article: PMC6834180] [PubMed: 31618813]
59. Kahle, K. T., Merner, N. D., Friedel, P., Silayeva, L., Liang, B., Khanna, A., Shang, Y., Lachance-Touchette, P., Bourassa, C., Levert, A., Dion, P. A., Walcott, B., Spiegelman, D., Dionne-Laporte, A., Hodgkinson, A., Awadalla, P., Nikbakht, H., Majewski, J., Cossette, P., Deeb, T. Z., Moss, S. J., Medina, I. and Rouleau, G. A. (2014) ‘ Genetically encoded impairment of neuronal KCC 2 cotransporter function in human idiopathic generalized epilepsy ’, EMBO reports. EMBO, 15(7), pp. 766–774. doi: 10.15252/embr.201438840. PMID: 24928908. [PMC free article: PMC4196980] [PubMed: 24928908]
60. Kandratavicius, L., Balista, P., Lopes-Aguiar, C., Ruggiero, R., Umeoka, E., Garcia-Cairasco, N., Bueno-Junior, L. and Leite, J. (2014) ‘Animal models of epilepsy: use and limitations’, Neuropsychiatric Disease and Treatment. Dove Medical Press Ltd., 10, p. 1693. doi: 10.2147/NDT.S50371. PMID: 25228809. [PMC free article: PMC4164293] [PubMed: 25228809]
61. Kauffman, M. A., Levy, E. M., Consalvo, D., Mordoh, J. and Kochen, S. (2008) ‘GABABR1 (G1465A) gene variation and temporal lobe epilepsy controversy: New evidence’, Seizure. Seizure, 17(6), pp. 567–571. doi: 10.1016/j.seizure.2007.12.006. PMID: 18255321. [PubMed: 18255321]
62. Keifer, J. (2021) ‘Comparative Genomics of the BDNF Gene, Non-Canonical Modes of Transcriptional Regulation, and Neurological Disease’, Molecular Neurobiology. Springer. doi: 10.1007/s12035-021-02306-z. PMID: 33517560. [PubMed: 33517560]
63. Khan, S., Nobili, L., Khatami, R., Loddenkemper, T., Cajochen, C., Dijk, D. J. and Eriksson, S. H. (2018) ‘Circadian rhythm and epilepsy’, The Lancet Neurology. Lancet Publishing Group, 17(12), pp. 1098–1108. doi: 10.1016/S1474-4422(18)30335-1. PMID: 30366868. [PubMed: 30366868]
64. Kiese, K., Jablonski, J., Boison, D. and Kobow, K. (2016) ‘Dynamic regulation of the adenosine kinase gene during early postnatal brain development and maturation’, Frontiers in Molecular Neuroscience. Frontiers Media S.A., 9(OCT2016). doi: 10.3389/fnmol.2016.00099. PMID: 27812320. [PMC free article: PMC5071315] [PubMed: 27812320]
65. Kim, J. H., Roberts, D. S., Hu, Y., Lau, G. C., Brooks-Kayal, A. R., Farb, D. H. and Russek, S. J. (2012) ‘Brain-derived neurotrophic factor uses CREB and Egr3 to regulate NMDA receptor levels in cortical neurons’, Journal of Neurochemistry. J Neurochem, 120(2), pp. 210–219. doi: 10.1111/j.1471-4159.2011.07555.x. PMID: 22035109. [PMC free article: PMC5116917] [PubMed: 22035109]
66. Klein, P., Dingledine, R., Aronica, E., Bernard, C., Blümcke, I., Boison, D., Brodie, M. J., Brooks-Kayal, A. R., Engel, J., Forcelli, P. A., Hirsch, L. J., Kaminski, R. M., Klitgaard, H., Kobow, K., Lowenstein, D. H., Pearl, P. L., Pitkänen, A., Puhakka, N., Rogawski, M. A., Schmidt, D., Sillanpää, M., Sloviter, R. S., Steinhäuser, C., Vezzani, A., Walker, M. C. and Löscher, W. (2018) ‘Commonalities in epileptogenic processes from different acute brain insults: Do they translate?’, Epilepsia. Blackwell Publishing Inc., 59(1),pp. 37–66. doi: 10.1111/epi.13965. PMID: 29247482. [PMC free article: PMC5993212] [PubMed: 29247482]
67. Kowiański, P., Lietzau, G., Czuba, E., Waśkow, M., Steliga, A. and Moryś, J. (2018) ‘BDNF: A Key Factor with Multipotent Impact on Brain Signaling and Synaptic Plasticity’, Cellular and Molecular Neurobiology. Springer New York LLC, pp. 579–593. doi: 10.1007/s10571-017-0510-4. PMID: 28623429. [PMC free article: PMC5835061] [PubMed: 28623429]
68. Kuzniewska, B., Nader, K., Dabrowski, M., Kaczmarek, L. and Kalita, K. (2016) ‘Adult Deletion of SRF Increases Epileptogenesis and Decreases Activity-Induced Gene Expression’, Molecular Neurobiology, 53(3), pp. 1478–1493. doi: 10.1007/s12035-014-9089-7. PMID: 25636686. [PMC free article: PMC4789231] [PubMed: 25636686]
69. Lafrenière, R. G., Rochefort, D. L., Chrétien, N., Rommens, J. M., Cochius, J. I., Kälviäinen, R., Nousiainen, U., Patry, G., Farrell, K., Söderfeldt, B., Federico, A., Hale, B. R., Cossio, O. H., Sørensen, T., Pouliot, M. A., Kmiec, T., Uldall, P., Janszky, J., Pranzatelli, M. R., Andermann, F., Andermann, E. and Rouleau, G. A. (1997) ‘Unstable insertion in the 5’ flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM1’, Nature Genetics. doi: 10.1038/ng0397-298. PMID: 9054946. [PubMed: 9054946]
70. Lambert, M., Jambon, S., Depauw, S. and David-Cordonnier, M. H. (2018) ‘Targeting transcription factors for cancer treatment’, Molecules. 23(6), pp. 1479. doi: 10.3390/molecules23061479. PMID: 29921764. [PMC free article: PMC6100431] [PubMed: 29921764]
71. Landry, J. R., Mager, D. L. and Wilhelm, B. T. (2003) ‘Complex controls: The role of alternative promoters in mammalian genomes’, Trends in Genetics. Elsevier Ltd, pp. 640–648. doi: 10.1016/j.tig.2003.09.014. PMID: 14585616. [PubMed: 14585616]
72. de Lange, I. M., Weuring, W., van ‘t Slot, R., Gunning, B., Sonsma, A. C. M., McCormack, M., de Kovel, C., van Gemert, L. J. J. M., Mulder, F., van Kempen, M. J. A., Knoers, N. V. A. M., Brilstra, E. H. and Koeleman, B. P. C. (2019) ‘Influence of common SCN1A promoter variants on the severity of SCN1A-related phenotypes’, Molecular Genetics and Genomic Medicine. doi: 10.1002/mgg3.727. PMID: 31144463. [PMC free article: PMC6625088] [PubMed: 31144463]
73. Lee, B., Dziema, H., Lee, K. H., Choi, Y. S. and Obrietan, K. (2007) ‘CRE-mediated transcription and COX-2 expression in the pilocarpine model of status epilepticus’, Neurobiology of Disease. Neurobiol Dis, 25(1), pp. 80–91. doi: 10.1016/j.nbd.2006.08.015. PMID: 17029965. [PMC free article: PMC1900429] [PubMed: 17029965]
74. Li, P., Fu, X., Smith, N. A., Ziobro, J., Curiel, J., Tenga, M. J., Martin, B., Freedman, S., Cea-Del Rio, C. A., Oboti, L., Tsuchida, T. N., Oluigbo, C., Yaun, A., Magge, S. N., O’Neill, B., Kao, A., Zelleke, T. G., Depositario-Cabacar, D. T., Ghimbovschi, S., Knoblach, S., Ho, C. Y., Corbin, J. G., Goodkin, H. P., Vicini, S., Huntsman, M. M., Gaillard, W. D., Valdez, G. and Liu, J. S. (2017) ‘Loss of CLOCK Results in Dysfunction of Brain Circuits Underlying Focal Epilepsy’, Neuron. Cell Press, 96(2), pp. 387–401.e6. doi: 10.1016/j.neuron.2017.09.044. PMID: 29024662. [PMC free article: PMC6233318] [PubMed: 29024662]
75. Liu, D., Stowie, A., de Zavalia, N., Leise, T., Pathak, S. S., Drewes, L. R., Davidson, A. J., Amir, S., Sonenberg, N. and Cao, R. (2018) ‘mTOR signaling in VIP neurons regulates circadian clock synchrony and olfaction’, Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences, 115(14), pp. E3296–E3304. doi: 10.1073/pnas.1721578115. PMID: 29555746. [PMC free article: PMC5889665] [PubMed: 29555746]
76. Lonze, B. E. and Ginty, D. D. (2002) ‘Function and regulation of CREB family transcription factors in the nervous system’, Neuron. Cell Press, pp. 605–623. doi: 10.1016/S0896-6273(02)00828-0. PMID: 12194863. [PubMed: 12194863]
77. Van Loo, K. M. J., Rummel, C. K., Pitsch, J., Müller, J. A., Bikbaev, A. F., Martinez-Chavez, E., Blaess, S., Dietrich, D., Heine, M., Becker, A. J. and Schoch, S. (2019) ‘Calcium channel subunit α2σ4 is regulated by early growth response 1 and facilitates epileptogenesis’, Journal of Neuroscience. Society for Neuroscience, 39(17), pp. 3175–3187. doi: 10.1523/JNEUROSCI.1731-18.2019. PMID: 30792272. [PMC free article: PMC6788814] [PubMed: 30792272]
78. Van Loo, K. M. J., Schaub, C., Pernhorst, K., Yaari, Y., Beck, H., Schoch, S. and Becker, A. J. (2012) ‘Transcriptional regulation of T-type calcium channel CaV3.2: Bi-directionality by early growth response 1 (Egr1) and repressor element 1 (RE-1) protein -silencing transcription factor (REST)’, Journal of Biological Chemistry, 287(19), pp. 15489–15501. doi: 10.1074/jbc.M111.310763. PMID: 22431737. [PMC free article: PMC3346130] [PubMed: 22431737]
79. Van Loo, K. M. J., Schaub, C., Pitsch, J., Kulbida, R., Opitz, T., Ekstein, D., Dalal, A., Urbach, H., Beck, H., Yaari, Y., Schoch, S. and Becker, A. J. (2015) ‘Zinc regulates a key transcriptional pathway for epileptogenesis via metal-regulatory transcription factor 1’, Nature Communications. Nature Publishing Group, 6, p. 8688. doi: 10.1038/ncomms9688. PMID: 26498180. [PMC free article: PMC4846312] [PubMed: 26498180]
80. López-López, D., Gómez-Nieto, R., Herrero-Turrión, M. J., García-Cairasco, N., Sánchez-Benito, D., Ludeña, M. D. and López, D. E. (2017) ‘Overexpression of the immediate-early genes Egr1, Egr2, and Egr3 in two strains of rodents susceptible to audiogenic seizures’, Epilepsy and Behavior. Academic Press Inc., 71(Pt B), pp. 226–237. doi: 10.1016/j.yebeh.2015.12.020. PMID: 26775236. [PubMed: 26775236]
81. Lösing, P., Niturad, C. E., Harrer, M., Reckendorf, C. M. Z., Schatz, T., Sinske, D., Lerche, H., Maljevic, S. and Knöll, B. (2017) ‘SRF modulates seizure occurrence, activity induced gene transcription and hippocampal circuit reorganization in the mouse pilocarpine epilepsy model’, Molecular Brain. Molecular Brain, 10(1), pp. 1–22. doi: 10.1186/s13041-017-0310-2. PMID: 28716058. [PMC free article: PMC5513048] [PubMed: 28716058]
82. Louhivuori, V., Arvio, M., Soronen, P., Oksanen, V., Paunio, T. and Castrén, M. L. (2009) ‘The Val66Met polymorphism in the BDNF gene is associated with epilepsy in fragile X syndrome’, Epilepsy Research. Epilepsy Res, 85(1), pp. 114–117. doi: 10.1016/j.eplepsyres.2009.01.005. PMID: 19394799. [PubMed: 19394799]
83. Lu, T., Aron, L., Zullo, J., Pan, Y., Kim, H., Chen, Y., Yang, T. H., Kim, H. M., Drake, D., Liu, X. S., Bennett, D. A., Colaiácovo, M. P. and Yankner, B. A. (2014) ‘REST and stress resistance in ageing and Alzheimer’s disease’, Nature. Nature Publishing Group, 507(7493), pp. 448–454. doi: 10.1038/nature13163. PMID: 24670762. [PMC free article: PMC4110979] [PubMed: 24670762]
84. Lund, I. V., Hu, Y., Raol, Y. S. H., Benham, R. S., Faris, R., Russek, S. J. and Brooks-Kayal, A. R. (2008) ‘BDNF selectively regulates GABAA receptor transcription by activation of the JAK/STAT pathway’, Science Signaling. Sci Signal, 1(41), pp. ra9. doi: 10.1126/scisignal.1162396. PMID: 18922788. [PMC free article: PMC2651003] [PubMed: 18922788]
85. Lunyak, V. V., Burgess, R., Prefontaine, G. G., Nelson, C., Sze, S. H., Chenoweth, J., Schwartz, P., Pevzner, P. A., Glass, C., Mandel, G. and Rosenfeld, M. G. (2002) ‘Corepressor-dependent silencing of chromosomal regions encoding neuronal genes’, Science. Science, 298(5599), pp. 1747–1752. doi: 10.1126/science.1076469. PMID: 12399542. [PubMed: 12399542]
86. Martínez-Levy, G. A., Rocha, L., Lubin, F. D., Alonso-Vanegas, M. A., Nani, A., Buentello-García, R. M., Pérez-Molina, R., Briones-Velasco, M., Recillas-Targa, F., Pérez-Molina, A., San-Juan, D., Cienfuegos, J. and Cruz-Fuentes, C. S. (2016) ‘Increased expression of BDNF transcript with exon VI in hippocampi of patients with pharmaco-resistant temporal lobe epilepsy’, Neuroscience. Elsevier Ltd, 314, pp. 12–21. doi: 10.1016/j.neuroscience.2015.11.046. PMID: 26621122. [PubMed: 26621122]
87. Mathern, G. W., Babb, T. L., Micevych, P. E., Blanco, C. E. and Pretorius, J. K. (1997) ‘Granule cell mRNA levels for BDNF, NGF, and NT-3 correlate with neuron losses or supragranular mossy fiber sprouting in the chronically damaged and epileptic human hippocampus’, Molecular and Chemical Neuropathology. Humana Press Inc., 30(1–2), pp. 53–76. doi: 10.1007/BF02815150. PMID: 9138429. [PubMed: 9138429]
88. Matos, H. de C., Koike, B. D. V., Pereira, W. dos S., de Andrade, T. G., Castro, O. W., Duzzioni, M., Kodali, M., Leite, J. P., Shetty, A. K. and Gitaí, D. L. G. (2018) ‘Rhythms of core clock genes and spontaneous locomotor activity in post-status Epilepticus model of mesial temporal lobe epilepsy’, Frontiers in Neurology. Frontiers Media S.A., 9, pp. 632. doi: 10.3389/fneur.2018.00632. PMID: 30116220. [PMC free article: PMC6082935] [PubMed: 30116220]
89. Maya-Vetencourt, J. F. (2013) ‘Activity-dependent NPAS4 expression and the regulation of gene programs underlying plasticity in the central nervous system’, Neural Plasticity. 683909. doi: 10.1155/2013/683909. PMID: 24024041. [PMC free article: PMC3759247] [PubMed: 24024041]
90. Maynard, K. R., Hill, J. L., Calcaterra, N. E., Palko, M. E., Kardian, A., Paredes, D., Sukumar, M., Adler, B. D., Jimenez, D. V., Schloesser, R. J., Tessarollo, L., Lu, B. and Martinowich, K. (2016) ‘Functional Role of BDNF Production from Unique Promoters in Aggression and Serotonin Signaling’, Neuropsychopharmacology. Nature Publishing Group, 41(8), pp. 1943–1955. doi: 10.1038/npp.2015.349. PMID: 26585288. [PMC free article: PMC4908631] [PubMed: 26585288]
91. Mazzuferi, M., Kumar, G., van Eyll, J., Danis, B., Foerch, P. and Kaminski, R. M. (2013) ‘Nrf2 defense pathway: Experimental evidence for its protective role in epilepsy’, Annals of Neurology. Ann Neurol, 74(4), pp. 560–568. doi: 10.1002/ana.23940. [PubMed: 23686862]
92. McClelland, S., Brennan, G. P., Dubé, C., Rajpara, S., Iyer, S., Richichi, C., Bernard, C. and Baram, T. Z. (2014) ‘The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes’, eLife, 3, p. e01267. doi: 10.7554/eLife.01267. PMID: 25117540. [PMC free article: PMC4129437] [PubMed: 25117540]
93. McClelland, S., Flynn, C., Dubé, C., Richichi, C., Zha, Q., Ghestem, A., Esclapez, M., Bernard, C. and Baram, T. Z. (2011) ‘Neuron-restrictive silencer factor-mediated hyperpolarization-activated cyclic nucleotide gated channelopathy in experimental temporal lobe epilepsy’, Annals of Neurology.  John Wiley and Sons Inc., 70(3), pp. 454–465. doi: 10.1002/ana.22479. PMID: 21905079. [PMC free article: PMC3177145] [PubMed: 21905079]
94. Mills, A. A. (2017) ‘The chromodomain helicase DNA-binding chromatin remodelers: Family traits that protect from and promote cancer’, Cold Spring Harbor Perspectives in Medicine.  Cold Spring Harbor Laboratory Press, 7(4), pp. a026450. doi: 10.1101/cshperspect.a026450. PMID: 28096241. [PMC free article: PMC5378010] [PubMed: 28096241]
95. Morris, T. A., Jafari, N., Rice, A. C., Vasconcelos, O. and DeLorenzo, R. J. (1999) ‘Persistent increased DNA-binding and expression of serum response factor occur with epilepsy-associated long-term plasticity changes’, Journal of Neuroscience. Society for Neuroscience, 19(19), pp. 8234–8243. doi: 10.1523/jneurosci.19-19-08234.1999. PMID: 10493724. [PMC free article: PMC6783053] [PubMed: 10493724]
96. Mucha, M., Ooi, L., Linley, J. E., Mordaka, P., Dalle, C., Robertson, B., Gamper, N. and Wood, I. C. (2010) ‘Transcriptional control of KCNQ channel genes and the regulation of neuronal excitability’, Journal of Neuroscience. J Neurosci, 30(40), pp. 13235–13245. doi: 10.1523/JNEUROSCI.1981-10.2010. PMID: 20926649. [PMC free article: PMC3044881] [PubMed: 20926649]
97. Nakayama, T., Ogiwara, I., Ito, K., Kaneda, M., Mazaki, E., Osaka, H., Ohtani, H., Inoue, Y., Fujiwara, T., Uematsu, M., Haginoya, K., Tsuchiya, S. and Yamakawa, K. (2010) ‘Deletions of SCN1A 5′ genomic region with promoter activity in dravet syndrome’, Human Mutation, 31(7), pp. 820–829. doi: 10.1002/humu.21275. PMID: 20506560. [PubMed: 20506560]
98. Naruse, Y., Aoki, T., Kojima, T. and Mori, N. (1999) ‘Neural restrictive silencer factor recruits mSin3 and histone deacetylase complex to repress neuron-specific target genes’, Proceedings of the National Academy of Sciences of the United States of America.  Proc Natl Acad Sci U S A, 96(24), pp. 13691–13696. doi: 10.1073/pnas.96.24.13691. PMID: 10570134. [PMC free article: PMC24126] [PubMed: 10570134]
99. Navarrete-Modesto, V., Orozco-Suárez, S., Alonso-Vanegas, M., Feria-Romero, I. A. and Rocha, L. (2019) ‘REST/NRSF transcription factor is overexpressed in hippocampus of patients with drug-resistant mesial temporal lobe epilepsy’, Epilepsy and Behavior. Academic Press Inc., 94, pp. 118–123. doi: 10.1016/j.yebeh.2019.02.012. PMID: 30903955. [PubMed: 30903955]
100. Pal, S., Gupta, R., Kim, H., Wickramasinghe, P., Baubet, V., Showe, L. C., Dahmane, N. and Davuluri, R. V. (2011) ‘Alternative transcription exceeds alternative splicing in generating the transcriptome diversity of cerebellar development’, Genome Research. Cold Spring Harbor Laboratory Press, 21(8), pp. 1260–1272. doi: 10.1101/gr.120535.111. PMID: 21712398. [PMC free article: PMC3149493] [PubMed: 21712398]
101. Paonessa, F., Latifi, S., Scarongella, H., Cesca, F. and Benfenati, F. (2013) ‘Specificity protein 1 (Sp1)-dependent activation of the synapsin I gene (SYN1) is modulated by RE1-silencing transcription factor (REST) and 5’-cytosine-phosphoguanine (CPG) methylation’, Journal of Biological Chemistry. J Biol Chem, 288(5), pp. 3227–3239. doi: 10.1074/jbc.M112.399782. PMID: 23250796. [PMC free article: PMC3561544] [PubMed: 23250796]
102. Paquette, A. J., Perez, S. E. and Anderson, D. J. (2000) ‘Constitutive expression of the neuron-restrictive silencer factor (NRSF)/REST in differentiating neurons disrupts neuronal gene expression and causes axon pathfinding errors in vivo’, Proceedings of the National Academy of Sciences of the United States of America.  Proc Natl Acad Sci U S A, 97(22), pp. 12318–12323. doi: 10.1073/pnas.97.22.12318. PMID: 11050251. [PMC free article: PMC17339] [PubMed: 11050251]
103. Park, H. and Poo, M. M. (2013) ‘Neurotrophin regulation of neural circuit development and function’, Nature Reviews Neuroscience. Nat Rev Neurosci, pp. 7–23. doi: 10.1038/nrn3379. PMID: 23254191. [PubMed: 23254191]
104. Patterson, K. P., Barry, J. M., Curran, M. M., Singh-Taylor, A., Brennan, G., Rismanchi, N., Page, M., Noam, Y., Holmes, G. L. and Baram, T. Z. (2017) ‘Enduring memory impairments provoked by developmental febrile seizures are mediated by functional and structural effects of neuronal restrictive silencing factor’, Journal of Neuroscience. Society for Neuroscience, 37(14), pp. 3799–3812. doi: 10.1523/JNEUROSCI.3748-16.2017. PMID: 28275159. [PMC free article: PMC5394897] [PubMed: 28275159]
105. Pitkänen, A. and Engel, J. (2014) ‘Past and Present Definitions of Epileptogenesis and Its Biomarkers’, Neurotherapeutics. Springer Science and Business Media, LLC, pp. 231–241. doi: 10.1007/s13311-014-0257-2. PMID: 24492975. [PMC free article: PMC3996117] [PubMed: 24492975]
106. Pitkänen, P. A. and Lukasiuk, K. (2011) ‘Mechanisms of epileptogenesis and potential treatment’, The Lancet Neurology. Elsevier Ltd, 10(2), pp. 173–186. doi: 10.1016/S1474-4422(10)70310-0. PMID: 21256455. [PubMed: 21256455]
107. Pruunsild, P., Kazantseval, A., Aid, T., Palm, K. and Timmusk, T. (2007) ‘Dissecting the human BDNF locus: Bidirectional transcription,  complex splicing, and multiple promoters’, Genomics. Elsevier, 90(3), pp. 397–406. doi: 10.1016/j.ygeno.2007.05.004. PMID: 17629449. [PMC free article: PMC2568880] [PubMed: 17629449]
108. Raible, D. J., Frey, L. C., Del Angel, Y. C., Carlsen, J., Hund, D., Russek, S. J., Smith, B. and Brooks-Kayal, A. R. (2015) ‘JAK/STAT pathway regulation of GABAA receptor expression after differing severities of experimental TBI’, Experimental Neurology. Academic Press Inc., 271, pp. 445–456. doi: 10.1016/j.expneurol.2015.07.001. PMID: 26172316. [PMC free article: PMC5969808] [PubMed: 26172316]
109. Rakhade, S. N., Yao, B., Ahmed, S., Asano, E., Beaumont, T. L., Shah, A. K., Draghici, S., Krauss, R., Chugani, H. T., Sood, S. and Loeb, J. A. (2005) ‘A common pattern of persistent gene activation in human neocortical epileptic foci’, Annals of Neurology. Ann Neurol, 58(5), pp. 736–747. doi: 10.1002/ana.20633. PMID: 16240350. [PubMed: 16240350]
110. Rambousek, L., Gschwind, T., Lafourcade, C., Paterna, J. C., Dib, L., Fritschy, J. M. and Fontana, A. (2020) ‘Aberrant expression of PAR bZIP transcription factors is associated with epileptogenesis, focus on hepatic leukemia factor’, Scientific Reports, 10(1), pp. 1–16. doi: 10.1038/s41598-020-60638-7. PMID: 32111960. [PMC free article: PMC7048777] [PubMed: 32111960]
111. Rawlings, J. S., Rosler, K. M. and Harrison, D. A. (2004) ‘The JAK/STAT signaling pathway’, Journal of Cell Science. J Cell Sci, 117(8), pp. 1281–1283. doi: 10.1242/jcs.00963. PMID: 15020666. [PubMed: 15020666]
112. Riedel, C. S., Georg, B., Jørgensen, H. L., Hannibal, J. and Fahrenkrug, J. (2018) ‘Mice Lacking EGR1 Have Impaired Clock Gene (BMAL1) Oscillation, Locomotor Activity, and Body Temperature’, Journal of Molecular Neuroscience. Springer New York LLC, 64(1), pp. 9–19. doi: 10.1007/s12031-017-0996-8. PMID: 29138967. [PubMed: 29138967]
113. Roberts, D. S., Raol, Y. H., Bandyopadhyay, S., Lund, I. V., Budreck, E. C., Passini, M. J., Wolfe, J. H., Brooks-Kayal, A. R. and Russek, S. J. (2005) ‘Egr3 stimulation of GABRA4 promoter activity as a mechanism for seizure-induced up-regulation of GABAA receptor α4 subunit expression’, Proceedings of the National Academy of Sciences of the United States of America, 102(33), pp. 11894–11899. doi: 10.1073/pnas.0501434102. PMID: 16091474. [PMC free article: PMC1187961] [PubMed: 16091474]
114. Rong, Y. and Baudry, M. (1996) ‘Seizure activity results in a rapid induction of nuclear factor-κB in adult but not juvenile rat limbic structures’, Journal of Neurochemistry. Blackwell Publishing Ltd, 67(2), pp. 662–668. doi: 10.1046/j.1471-4159.1996.67020662.x. PMID: 8764593. [PubMed: 8764593]
115. Ruíz-Díaz, A., Manjarrez, J., Nava-Ruíz, C., Zaga-Clavellina, V., Flores-Espinosa, P., Díaz-Ruíz, A., Yescas-Gómez, P. and Méndez-Armenta, M. (2019) ‘Expression of nuclear factor-erythroid 2-related factor 2 in rat brain following the administration of kainic acid and pentylenetetrazole.’, Neuroreport. Neuroreport, 30(5), pp. 358–362. doi: 10.1097/WNR.0000000000001207. PMID: 30724852. [PubMed: 30724852]
116. Sabatini, P. V., Speckmann, T., Nian, C., Glavas, M. M., Wong, C. K., Yoon, J. S., Kin, T., Shapiro, A. M. J., Gibson, W. T., Verchere, C. B. and Lynn, F. C. (2018) ‘Neuronal PAS Domain Protein 4 Suppression of Oxygen Sensing Optimizes Metabolism during Excitation of Neuroendocrine Cells’, Cell Reports. Elsevier B.V., 22(1), pp. 163–174. doi: 10.1016/j.celrep.2017.12.033. PMID: 29298418. [PubMed: 29298418]
117. Sakata, K., Woo, N. H., Martinowich, K., Greene, J. S., Schloesser, R. J., Shen, L. and Lu, B. (2009) ‘Critical role of promoter IV-driven BDNF transcription in GABAergic transmission and synaptic plasticity in the prefrontal cortex’, Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences, 106(14), pp. 5942–5947. doi: 10.1073/pnas.0811431106. PMID: 19293383. [PMC free article: PMC2667049] [PubMed: 19293383]
118. Sankar, R., Shin, D., Mazarati, A. M., Liu, H., Katsumori, H., Lezama, R. and Wasterlain, C. G. (2000) ‘Epileptogenesis after status epilepticus reflects age- and model-dependent plasticity’, Annals of Neurology, 48(4), pp. 580–589. doi: 10.1002/1531-8249(200010)48:4<580::AID-ANA4>3.0.CO;2-B. PMID: 11026441. [PubMed: 11026441]
119. Schauwecker, P. E. (2000) ‘Seizure-induced neuronal death is associated with induction of c-Jun N-terminal kinase and is dependent on genetic background’, Brain Research. Brain Res, 884(1–2), pp. 116–128. doi: 10.1016/S0006-8993(00)02888-2. PMID: 11082493. [PubMed: 11082493]
120. Searle, P. F. (1990) ‘Zinc dependent binding of a liver nuclear factor to metal response element MRE-a of the mouse metallothionein-l gene and variant sequences’, Nucleic Acids Research, 18(16), pp. 4683–4690. doi: 10.1093/nar/18.16.4683. PMID: 2395635. [PMC free article: PMC331918] [PubMed: 2395635]
121. Shekh-Ahmad, T., Eckel, R., Dayalan Naidu, S., Higgins, M., Yamamoto, M., Dinkova-Kostova, A. T., Kovac, S., Abramov, A. Y. and Walker, M. C. (2018) ‘KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy.’, Brain : a journal of neurology. Brain, 141(5), pp. 1390–1403. doi: 10.1093/brain/awy071. PMID: 29538645. [PubMed: 29538645]
122. Shen, N., Zhu, X., Lin, H., Li, J., Li, L., Niu, F., Liu, A., Wu, X., Wang, Y. and Liu, Y. (2016) ‘Role of BDNF Val66Met functional polymorphism in temporal lobe epilepsy’, International Journal of Neuroscience. Taylor and Francis Ltd, 126(5), pp. 436–441. doi: 10.3109/00207454.2015.1026967. PMID: 26000807. [PubMed: 26000807]
123. Shin, C., McNamara, J. O., Morgan, J. I., Curran, T. and Cohen, D. R. (1990) ‘Induction of c-fos mRNA Expression by Afterdischarge in the Hippocampus of Naive and Kindled Rats’, Journal of Neurochemistry. J Neurochem, 55(3), pp. 1050–1055. doi: 10.1111/j.1471-4159.1990.tb04595.x. PMID: 2117045. [PubMed: 2117045]
124. Sikdar, S. and Datta, S. (2017) ‘A novel statistical approach for identification of the master regulator transcription factor’, BMC Bioinformatics. BioMed Central Ltd., 18(1), p. 79. doi: 10.1186/s12859-017-1499-x. PMID: 28148240. [PMC free article: PMC5288875] [PubMed: 28148240]
125. Simonato, M., Hosford, D. A., Labiner, D. M., Shin, C., Mansbach, H. H. and McNamara, J. O. (1991) ‘Differential expression of immediate early genes in the hippocampus in the kindling model of epilepsy’, Molecular Brain Research. Brain Res Mol Brain Res, 11(2), pp. 115–124. doi: 10.1016/0169-328X(91)90113-C. PMID: 1661808. [PubMed: 1661808]
126. Snyder-Keller, A. M. and Pierson, M. G. (1992) ‘Audiogenic seizures induce c-fos in a model of developmental epilepsy’, Neuroscience Letters. Neurosci Lett, 135(1), pp. 108–112. doi: 10.1016/0304-3940(92)90147-Y. PMID: 1542426. [PubMed: 1542426]
127. Steiger, J. L., Bandyopadhyay, S., Farb, D. H. and Russek, S. J. (2004) ‘cAMP response element-binding protein, activating transcription factor-4, and upstream stimulatory factor differentially control hippocampal GABA BR1a and GABABR1b subunit gene expression through alternative promoters’, Journal of Neuroscience.  Society for Neuroscience, 24(27), pp. 6115–6126. doi: 10.1523/JNEUROSCI.1200-04.2004. PMID: 15240803. [PMC free article: PMC6729677] [PubMed: 15240803]
128. Stuart, G. W., Searle, P. F. and Palmiter, R. D. (1985) ‘Identification of multiple metal regulatory elements in mouse metallothionein-I promoter by assaying synthetic sequences’, Nature, 317(6040), pp. 828–831. doi: 10.1038/317828a0. PMID: 4058587. [PubMed: 4058587]
129. Suh, S. W., Thompson, R. B. and Frederickson, C. J. (2001) ‘Loss of vesicular zinc and appearance of perikaryal zinc after seizures induced by pilocarpine.’, Neuroreport, 12(7), pp. 1523–5. Available at: http://www​.ncbi.nlm.nih​.gov/pubmed/11388441PMID: 11388441. [PubMed: 11388441]
130. Tai, T. Y., Warner, L. N., Jones, T. D., Jung, S., Concepcion, F. A., Skyrud, D. W., Fender, J., Liu, Y., Williams, A. D., Neumaier, J. F., D’Ambrosio, R. and Poolos, N. P. (2017) ‘Antiepileptic action of c-Jun N-terminal kinase (JNK) inhibition in an animal model of temporal lobe epilepsy’, Neuroscience. Elsevier Ltd, 349, pp. 35–47. doi: 10.1016/j.neuroscience.2017.02.024. PMID: 28237815. [PMC free article: PMC5386321] [PubMed: 28237815]
131. Tavera-Montañez, C., Hainer, S. J., Cangussu, D., Gordon, S. J. V., Xiao, Y., Reyes-Gutierrez, P., Imbalzano, A. N., Navea, J. G., Fazzio, T. G. and Padilla-Benavides, T. (2019) ‘The classic metal-sensing transcription factor MTF1 promotes myogenesis in response to copper’, The FASEB Journal. NLM (Medline), 33(12), pp. 14556–14574. doi: 10.1096/fj.201901606R. PMID: 31690123. [PMC free article: PMC6894080] [PubMed: 31690123]
132. Teocchi, M. A., Ferreira, A. É. D., da Luz de Oliveira, E. P., Tedeschi, H. and D’Souza-Li, L. (2013) ‘Hippocampal gene expression dysregulation of Klotho, nuclear factor kappa B and tumor necrosis factor in temporal lobe epilepsy patients’, Journal of Neuroinflammation.  J Neuroinflammation, 10, pp. 53. doi: 10.1186/1742-2094-10-53. PMID: 23634661. [PMC free article: PMC3651326] [PubMed: 23634661]
133. Timmusk, T., Palm, K., Metsis, M., Reintam, T., Paalme, V., Saarma, M. and Persson, H. (1993) ‘Multiple promoters direct tissue-specific expression of the rat BDNF gene’, Neuron. Neuron, 10(3), pp. 475–489. doi: 10.1016/0896-6273(93)90335-O. PMID: 8461137. [PubMed: 8461137]
134. Tsortouktzidis, D., Schulz, H., Hamed, M., Vatter, H., Surges, R., Schoch, S., Sander, T., Becker, A. J. and van Loo, K. M. J. (2021) ‘Gene expression analysis in epileptic hippocampi reveals a promoter haplotype conferring reduced aldehyde dehydrogenase 5a1 expression and responsiveness’, Epilepsia. 62(1), pp. e29-e34. doi: 10.1111/epi.16789. PMID: 33319393. [PubMed: 33319393]
135. Urak, L., Feucht, M., Fathi, N., Hornik, K. and Fuchs, K. (2006) ‘A GABRB3 promoter haplotype associated with childhood absence epilepsy impairs transcriptional activity’, Human Molecular Genetics, 15(16), pp. 2533–2541. doi: 10.1093/hmg/ddl174. PMID: 16835263. [PubMed: 16835263]
136. Uvarov, P., Ludwig, A., Markkanen, M., Pruunsild, P., Kaila, K., Delpire, E., Timmusk, T., Rivera, C. and Airaksinen, M. S. (2007) ‘A novel N-terminal isoform of the neuron-specific K-Cl cotransporter KCC2’, Journal of Biological Chemistry. J Biol Chem, 282(42), pp. 30570–30576. doi: 10.1074/jbc.M705095200. PMID: 17715129. [PubMed: 17715129]
137. Vialou, V., Feng, J., Robison, A. J., Ku, S. M., Ferguson, D., Scobie, K. N., Mazei-Robison, M. S., Mouzon, E. and Nestler, E. J. (2012) ‘Serum response factor and cAMP response element binding protein are both required for cocaine induction of ΔFosB’, Journal of Neuroscience. J Neurosci, 32(22), pp. 7577–7584. doi: 10.1523/JNEUROSCI.1381-12.2012. PMID: 22649236. [PMC free article: PMC3370956] [PubMed: 22649236]
138. Vialou, V., Maze, I., Renthal, W., LaPlant, Q. C., Watts, E. L., Mouzon, E., Ghose, S., Tamminga, C. A. and Nestler, E. J. (2010) ‘Serum response factor promotes resilience to chronic social stress through the induction of ΔFosB’, Journal of Neuroscience. J Neurosci, 30(43), pp. 14585–14592. doi: 10.1523/JNEUROSCI.2496-10.2010. PMID: 20980616. [PMC free article: PMC2977979] [PubMed: 20980616]
139. Virtaneva, K., D’Amato, E., Miao, J., Koskiniemi, M., Norio, R., Avanzini, G., Franceschetti, S., Michelucci, R., Tassinari, C. A., Omer, S., Pennacchio, L. A., Myers, R. M., Dieguez-Lucena, J. L., Krahe, R., De La Chapelle, A. and Lehesjoki, A. E. (1997) ‘Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1’, Nature Genetics. doi: 10.1038/ng0497-393. PMID: 9090386. [PubMed: 9090386]
140. Wang, D., Ren, M., Guo, J., Yang, G., Long, X., Hu, R., Shen, W., Wang, X., Zeng, K. and Chapouthier, G. (2014) ‘The inhibitory effects of Npas4 on seizures in pilocarpine-induced epileptic rats’, PLoS ONE. Public Library of Science, 9(12). doi: 10.1371/journal.pone.0115801. PMID: 25536221. [PMC free article: PMC4275263] [PubMed: 25536221]
141. Wang, H., Yao, G., Li, L., Ma, Z., Chen, J. and Chen, W. (2020) ‘LncRNA-UCA1 inhibits the astrocyte activation in the temporal lobe epilepsy via regulating the JAK/STAT signaling pathway’, Journal of Cellular Biochemistry. Wiley-Liss Inc., 121(10), pp. 4261–4270. doi: 10.1002/jcb.29634. PMID: 31909503. [PubMed: 31909503]
142. Wang, J., Lin, Z., Liu, L., Xu, H., Shi, Y., Yi, Y., He, N. and Liao, W. (2017) ‘Epilepsy-associated genes’, Seizure, 44, pp. 11–20. doi: 10.1016/j.seizure.2016.11.030. PMID: 28007376. [PubMed: 28007376]
143. Watanabe, Y., Johnson, R. S., Butler, L. S., Binder, D. K., Spiegelman, B. M., Papaioannou, V. E. and McNamara, J. O. (1996) ‘Null mutation of c-fos impairs structural and functional plasticities in the kindling model of epilepsy’, Journal of Neuroscience. Society for Neuroscience, pp. 3827–3836. doi: 10.1523/jneurosci.16-12-03827.1996. PMID: 8656277. [PMC free article: PMC6578612] [PubMed: 8656277]
144. Wilson, M. M., Henshall, D. C., Byrne, S. M. and Brennan, G. P. (2021) ‘Chd2-related cns pathologies’, International Journal of Molecular Sciences. doi: 10.3390/ijms22020588. PMID: 33435571. [PMC free article: PMC7827033] [PubMed: 33435571]
145. Woitecki, A. M. H., Müller, J. A., van Loo, K. M. J., Sowade, R. F., Becker, A. J. and Schoch, S. (2016) ‘Identification of synaptotagmin 10 as effector of NPAS4-mediated protection from excitotoxic neurodegeneration’, Journal of Neuroscience. Society for Neuroscience, 36(9), pp. 2561–2570. doi: 10.1523/JNEUROSCI.2027-15.2016. PMID: 26936998. [PMC free article: PMC6604865] [PubMed: 26936998]
146. Won, S. J., Ko, H. W., Kim, E. Y., Park, E. C., Huh, K., Jung, N. P., Choi, I., Oh, Y. K., Shin, H. C. and Gwag, B. J. (1999) ‘Nuclear factor kappa B-mediated kainate neurotoxicity in the rat and hamster hippocampus’, Neuroscience. Neuroscience, 94(1), pp. 83–91. doi: 10.1016/S0306-4522(99)00196-7. PMID: 10613499. [PubMed: 10613499]
147. You, J. C., Muralidharan, K., Park, J. W., Petrof, I., Pyfer, M. S., Corbett, B. F., Lafrancois, J. J., Zheng, Y., Zhang, X., Mohila, C. A., Yoshor, D., Rissman, R. A., Nestler, E. J., Scharfman, H. E. and Chin, J. (2017) ‘Epigenetic suppression of hippocampal calbindin-D28k by ΔfosB drives seizure-related cognitive deficits’, Nature Medicine. Nature Publishing Group, 23(11), pp. 1377–1383. doi: 10.1038/nm.4413. PMID: 29035369. [PMC free article: PMC5747956] [PubMed: 29035369]
148. Younus, I. and Reddy, D. S. (2018) ‘A resurging boom in new drugs for epilepsy and brain disorders’, Expert Review of Clinical Pharmacology. Taylor and Francis Ltd, 11(1), pp. 27–45. doi: 10.1080/17512433.2018.1386553. PMID: 28956955. [PubMed: 28956955]
149. Zhu, X., Han, X., Blendy, J. A. and Porter, B. E. (2012) ‘Decreased CREB levels suppress epilepsy’, Neurobiology of Disease. Neurobiol Dis, 45(1), pp. 253–263. doi: 10.1016/j.nbd.2011.08.009. PMID: 21867753. [PMC free article: PMC4011562] [PubMed: 21867753]
150. Zweier, M., Gregor, A., Zweier, C., Engels, H., Sticht, H., Wohlleber, E., Bijlsma, E. K., Holder, S. E., Zenker, M., Rossier, E., Grasshoff, U., Johnson, D. S., Robertson, L., Firth, H. V., Kraus, C., Ekici, A. B., Reis, A. and Rauch, A. (2010) ‘Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression’, Human Mutation. 31(6), pp. 722–733. doi: 10.1002/humu.21253. PMID: 20513142. [PubMed: 20513142]