Epileptogenesis-related genes revisited

https://doi.org/10.1016/S0079-6123(06)58011-2Get rights and content

Abstract

The main goal of this study was to identify common features in the molecular response to epileptogenic stimuli across different animal models of epileptogenesis. Therefore, we compared the currently available literature on the global analysis of gene expression following epileptogenic insult to search for (i) highly represented functional gene classes (GO terms) within data sets, and (ii) individual genes that appear in several data sets, and therefore, might be of particular importance for the development of epilepsy due to different etiologies. We focused on two well-described models of brain insult that induce the development of spontaneous seizures in experimental animals: status epilepticus and traumatic brain injury. Additionally, a few papers describing gene expression in rat and human epileptic tissue were included for comparison. Our analysis revealed that epileptogenic insults induce significant changes in gene expression within a subset of pre-defined GO terms, that is, in groups of functionally linked genes. We also found individual genes for which expression changed across different models of epileptogenesis. Alterations in gene expression appear time-specific and underlie a number of processes that are linked with epileptogenesis, such as cell death and survival, neuronal plasticity, or immune response. Particularly, our analysis highlighted alterations in gene expression in glial cells as well as in genes involved in the immune response, which suggests the importance of gliosis and immune reaction in epileptogenesis.

Introduction

Epilepsies are the second most-common neurologic disorder after stroke (Porter, 1993). It is estimated that approximately 0.8% of the population is affected by some form of epilepsy. In approximately 30% of cases, epilepsy is a result of an insult to the brain, such as traumatic brain injury (TBI), stroke, brain infection, prolonged complex febrile seizures, or status epilepticus (SE) (Hauser, 1997). In such cases, the initial insult is commonly followed by a latency period (epileptogenesis) that can last for months or years before the appearance of spontaneous seizures and epilepsy diagnosis (Pitkanen and Sutula, 2002).

During the latency period, several phenomena can occur in parallel, including neuronal loss, dendritic and axonal plasticity, neurogenesis, gliosis, remodeling of the extracellular matrix, and alterations in gene expression (Parent et al., 1997; Bazan and Serou, 1999; Clark and Wilson, 1999; Coulter and DeLorenzo, 1999; Endo et al., 1999; Covolan et al., 2000; Wu et al., 2000). Such phenomena might reflect a response of the brain to the insult. At least some of the molecular alterations are also involved in the chronic remodeling of neuronal circuits, which eventually leads to the development of epilepsy. Hypothetically, identification of key molecular changes will provide a better understanding of epileptogenesis and point to targets that can be used to modify the epileptogenic process and, in the most optimistic scenario, develop antiepileptogenic treatments.

Studies of gene expression following potentially epileptogenic events like SE, ischemia, or TBI have a long history, and a vast amount of data has been gathered using traditional molecular biology methods (Nedivi et al., 1993; Koistinaho and Hokfelt, 1997; Zagulska-Szymczak et al., 2001). Nevertheless, these studies have focused on a limited number of pre-selected genes at a time. Recent technologic developments allow for the analysis of gene expression at the level of the whole transcriptome (microarrays and serial analysis of gene expression), and thus, provide an unbiased insight into the ensemble of molecular events that occur in the brain following various types of injuries. Brain trauma can trigger alterations in gene expression that partly represent a normal physiologic response to the injury. On the other hand, each of the components of the pathologic circuitry reorganization requires an expression of a particular set of genes.

Just a few years ago, there were less than a handful of large-scale molecular profiling studies of epileptogenic brain (Hendriksen et al., 2001; Elliott et al., 2003; Lukasiuk et al., 2003). A conspicuous feature of these data is that there is a very little overlap between the data sets of genes with altered expression (Lukasiuk and Pitkanen, 2004). This might be related to technical issues, including the brain area or cell population selected for the analysis, the use of different experimental platforms with a limited selection of gene probes, the limited sensitivity of methods for global analysis of gene expression in brain tissue, and the use of different kinds of animal models at different stages of disease development (Lukasiuk and Pitkanen, 2004). There are also specific problems in data interpretation related to analysis of the whole transcriptome. For example, there is only a limited amount of information or no information available on the biologic function of most of the altered genes.

The recent explosion in the application of large-scale molecular profiling in studies investigating the consequences of epileptogenic brain insults as well as advances in bioinformatics has provided a large amount of new data that can be analyzed with novel tools to extract the meaningful information from the noise. For example, databases allowing functional annotations of genes are updated regularly (e.g., http://www.geneontology.org/), and innovative tools that allow for the analysis of gene expression data have been developed.

The present study was fueled by the idea that an unbiased analysis of gene expression will highlight the most-prominent metabolic pathways or other phenomena that underlie reorganization of the epileptogenic circuitry in the brain, and eventually, guide our efforts to identify candidate targets for antiepileptogenic treatments. Here, we reanalysed and compared lists of genes that are regulated by potentially epileptogenic stimuli and are available from publications. We particularly searched for (i) highly represented functional gene classes (GO terms) within the data sets, and (ii) individual genes that appeared in several data sets, and therefore, could be of particular importance for epileptogenesis.

Section snippets

Selection of papers for analysis and creation of gene lists

The main goal of this project was to identify common features in the molecular responses to epileptogenic stimuli across different animal models. Therefore, papers that describe alterations in the transcriptome following SE or TBI, which are known to trigger epileptogenesis in experimental animals, were selected for analysis, as summarized in Table 1. A few papers describing gene expression in epileptic tissue were also included for comparison. The analysis required extensive database searches,

Results and discussion

Our analysis revealed that various epileptogenic insults induce statistically significant changes in gene expression in functionally linked genes that were predefined as GO terms. The number of over-represented GO terms associated with a particular gene list was, however, variable. In some cases, many biologic or molecular processes were indicated, whereas others had no significant changes. The lack of significant findings in some data sets could relate, for example, to the small number of

Concluding remarks

We used novel bioinformatics tools to compare the available literature on global analysis of gene expression following epileptogenic insults. We aimed at identifying (i) highly represented functional gene classes within the data sets and (ii) individual genes that appear in several data sets, and therefore, might be of particular importance for epileptogenesis. Analysis of their function indicated some trends in post-injury gene expression that have been somewhat underappreciated in the

Abbreviations

    AHS

    ammon horn sclerosis

    CCI

    controlled cortical impact injury

    FPI

    lateral fluid percussion injury

    GO

    gene ontology

    SE

    status epilepticus

    TBI

    traumatic brain injury

    TLE

    temporal-lobe epilepsy

Acknowledgments

The work was supported by The Polish State Committee for Scientific Research grant No. 2 P04A 052 26 (to K.L.) and the Academy of Finland, the Sigrid Juselius Foundation, the Finnish Cultural Foundation, and the Paulo Foundation (to A.P.). We apologize to all distinguished colleagues whose original articles are not cited in this review. Due to the vast number of issues discussed and space constraints, we were forced to refer only to databases and review articles whenever possible.

References (85)

  • M. Khurgel et al.

    Activation of astrocytes during epileptogenesis in the absence of neuronal degeneration

    Neurobiol. Dis.

    (1995)
  • S.K. Kim et al.

    Gene expression profile analyses of cortical dysplasia by cDNA arrays

    Epilepsy Res.

    (2003)
  • S.Y. Kim et al.

    Osteopontin in kainic acid-induced microglial reactions in the rat brain

    Mol. Cells

    (2002)
  • N. Kobori et al.

    Altered expression of novel genes in the cerebral cortex following experimental brain injury

    Brain Res. Mol. Brain Res.

    (2002)
  • J.Y. Lee et al.

    Zinc released from metallothionein-iii may contribute to hippocampal CA1 and thalamic neuronal death following acute brain injury

    Exp. Neurol.

    (2003)
  • C. Lindwall et al.

    Retrograde axonal transport of JNK signaling molecules influence injury induced nuclear changes in p-c-Jun and ATF3 in adult rat sensory neurons

    Mol. Cell Neurosci.

    (2005)
  • S.A. Mahoney et al.

    Stabilization of neurites in cerebellar granule cells by transglutaminase activity: identification of midkine and galectin-3 as substrates

    Neuroscience

    (2000)
  • P. Montpied et al.

    Hippocampal alterations of apolipoprotein E and D mRNA levels in vivo and in vitro following kainate excitotoxicity

    Epilepsy Res.

    (1999)
  • A.M. Munoz et al.

    Glial overexpression of heme oxygenase-1: a histochemical marker for early stages of striatal damage

    J. Chem. Neuroanat.

    (2005)
  • K. Namikawa et al.

    Enhanced expression of 14-3-3 family members in injured motoneurons

    Brain Res. Mol. Brain Res.

    (1998)
  • G.M. Pasinetti et al.

    Complement C1qB and C4 mRNAs responses to lesioning in rat brain

    Exp. Neurol.

    (1992)
  • P. Pesheva et al.

    Nerve growth factor-mediated expression of galectin-3 in mouse dorsal root ganglion neurons

    Neurosci. Lett.

    (2000)
  • A. Pitkanen et al.

    Post-traumatic epilepsy induced by lateral fluid-percussion injury in rats

  • A. Pitkanen et al.

    Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal-lobe epilepsy

    Lancet Neurol.

    (2002)
  • G.A. Rabinovich et al.

    Galectins and their ligands: amplifiers, silencers or tuners of the inflammatory response?

    Trends Immunol.

    (2002)
  • M.A. Salazar et al.

    Tuba, a novel protein containing bin/amphiphysin/Rvs and Dbl homology domains, links dynamin to regulation of the actin cytoskeleton

    J. Biol. Chem.

    (2003)
  • M. Sayyah et al.

    Antiepileptogenic and anticonvulsant activity of interleukin-1 beta in amygdala-kindled rats

    Exp. Neurol.

    (2005)
  • B. Voutsinos-Porche et al.

    Temporal patterns of the cerebral inflammatory response in the rat lithium-pilocarpine model of temporal lobe epilepsy

    Neurobiol. Dis.

    (2004)
  • J. Williams et al.

    Krox20 may play a key role in the stabilization of long-term potentiation

    Brain Res. Mol. Brain. Res.

    (1995)
  • E. Yakubov et al.

    Overexpression of genes in the CA1 hippocampus region of adult rat following episodes of global ischemia

    Brain Res. Mol. Brain Res.

    (2004)
  • S. Zagulska-Szymczak et al.

    Kainate-induced genes in the hippocampus: lessons from expression patterns

    Neurochem. Int.

    (2001)
  • C. Zhang et al.

    Ets-1 protects vascular smooth muscle cells from undergoing apoptosis by activating p21WAF1/Cip1: ETS-1 regulates basal and and inducible p21WAF1/Cip: ETS-1 regulates basal and inducible p21WAF1/Cip1 transcription via distinct cis-acting elements in the p21WAF/Cip1 promoter

    J. Biol. Chem.

    (2003)
  • W.C. Abraham et al.

    The role of immediate early genes in the stabilization of long-term potentiation

    Mol. Neurobiol.

    (1991)
  • M. Arai et al.

    Identification of epilepsy-related genes by gene expression profiling in the hippocampus of genetically epileptic rat

    Brain Res. Mol. Brain Res.

    (2003)
  • N.G. Bazan et al.

    Second messengers, long-term potentiation, gene expression and epileptogenesis

    Adv. Neurol.

    (1999)
  • A.J. Becker et al.

    Transcriptional profiling in human epilepsy: expression array and single cell real-time qRT-PCR analysis reveal distinct cellular gene regulation

    Neuroreport

    (2002)
  • A.J. Becker et al.

    Correlated stage-and subfield-associated hippocampal gene expression patterns in experimental and human temporal lobe epilepsy

    Eur. J. Neurosci.

    (2003)
  • T. Beissbarth et al.

    GOstat: find statistically overrepresented Gene Ontologies within a group of genes

    Bioinformatics

    (2004)
  • H.J. Bidmon et al.

    Heat shock protein-27 is upregulated in the temporal cortex of patients with epilepsy

    Epilepsia

    (2004)
  • D.K. Binder

    The role of BDNF in epilepsy and other diseases of the mature nervous system

    Adv. Exp. Med. Biol.

    (2004)
  • S. Clark et al.

    Mechanisms of epileptogenesis

    Adv. Neurol.

    (1999)
  • D.A. Coulter et al.

    Basic mechanisms of status epilepticus

    Adv. Neurol.

    (1999)
  • Cited by (70)

    • Epilepsy

      2022, Neurobiology of Brain Disorders: Biological Basis of Neurological and Psychiatric Disorders, Second Edition
    • Molecular tools for the characterization of seizure susceptibility in genetic rodent models of epilepsy

      2021, Epilepsy and Behavior
      Citation Excerpt :

      The molecular mechanisms underlying epileptogenesis are thought to be associated with altered expression of gene groups [66], and the microarray has been the preferred platform for their gene expression analysis [61,67]. In the last 20 years, there have been published more than 40 large-scale gene expression studies on epileptic tissue obtained from resection of the epileptogenic zone [11,61,66–79]. Furthermore, mainly in the last decade, some works aimed to study the potential genes or pathways associated with epilepsy based on micro RNA (miRNA) expression profiles [80–84].

    • Mechanisms of epileptogenesis and preclinical approach to antiepileptogenic therapies

      2018, Pharmacological Reports
      Citation Excerpt :

      Heterogeneity of tissue alterations (listed in the above section) occurring in the epileptogenic brain suggests that various molecular mechanisms are involved in these changes. Analysis of studies on the global alteration in gene expression following epileptogenic insult such as SE and TBI in animals, revealed that genes involved in cell death and survival, neuronal plasticity, adhesion, inflammation or immune response are altered in these models already at the early postinjury phase [79–81]. Alterations in expression of over 100 genes throughout epileptogenesis were found, indicating involvement of e.g. proteolytic cascades, transforming growth factor ß (TGF-ß) and insulin-like growth factor 1 (IGF-1) signalling as well as p38MAPK, Jak-STAT, PI3 K and mTOR signalling pathways [6,82].

    • Epilepsy

      2014, Neurobiology of Brain Disorders: Biological Basis of Neurological and Psychiatric Disorders
    View all citing articles on Scopus
    View full text