Seizure: European Journal of Epilepsy
Volume 19, Issue 6 , Pages 335-338, July 2010

Temporal Lobe Epilepsy and Matrix Metalloproteinase 9: A tempting relation but negative genetic association

  • Kjell Heuser

      Affiliations

    • Department of Neurology, Division for Clinical Neuroscience, Oslo University Hospital, Rikshospitalet, and University of Oslo, Norway
    • Corresponding Author InformationCorresponding author. Tel.: +47 230 70472; fax: +47 230 70490.
    • ,
  • Eystein Hellstrøm Hoddevik

      Affiliations

    • Centre for Molecular Biology and Neuroscience (CMBN), University of Oslo and Oslo University Hospital, Norway
    • ,
  • Erik Taubøll

      Affiliations

    • Department of Neurology, Division for Clinical Neuroscience, Oslo University Hospital, Rikshospitalet, and University of Oslo, Norway
    • ,
  • Leif Gjerstad

      Affiliations

    • Department of Neurology, Division for Clinical Neuroscience, Oslo University Hospital, Rikshospitalet, and University of Oslo, Norway
    • ,
  • Ulf Indahl

      Affiliations

    • Centre for Integrative Genetics (CIGENE), Norwegian University of Life Sciences, Department of Animal and Aquacultural Sciences, Ås, Norway
    • ,
  • Leszek Kaczmarek

      Affiliations

    • Department of Molecular and Cellular Neurobiology, Nencki Institute, Warsaw, Poland
    • ,
  • Paul R. Berg

      Affiliations

    • Centre for Integrative Genetics (CIGENE), Norwegian University of Life Sciences, Department of Animal and Aquacultural Sciences, Ås, Norway
    • ,
  • Sigbjørn Lien

      Affiliations

    • Centre for Integrative Genetics (CIGENE), Norwegian University of Life Sciences, Department of Animal and Aquacultural Sciences, Ås, Norway
    • ,
  • Erlend A. Nagelhus

      Affiliations

    • Centre for Molecular Biology and Neuroscience (CMBN), University of Oslo and Oslo University Hospital, Norway
    • ,
  • Ole Petter Ottersen

      Affiliations

    • Centre for Molecular Biology and Neuroscience (CMBN), University of Oslo and Oslo University Hospital, Norway

Received 25 February 2010; received in revised form 3 May 2010; accepted 7 May 2010. published online 04 June 2010.

Article Outline

Abstract 

Objective

Neuroplasticity can be defined as the ability of the brain to adapt to environmental impacts. These adaptations include synapse formation and elimination, cortical reorganization, and neurogenesis. In epilepsy these mechanisms may become detrimental and contribute to disease progression. It has been proposed that Matrix Metalloproteinase 9 (MMP-9), a proteinase that cleaves extracellular matrix molecules, may be critically involved in aberrant synaptic formation in hippocampi of patients with Temporal Lobe Epilepsy (TLE). Here we present a case–control study designed to identify possible variants of the MMP-9 gene associated with human TLE.

Material and methods

218 Norwegian patients with TLE and 181 ethnically matched controls were compared in our association analysis. We also studied associations within two subgroups of TLE – Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis (MTLE-HS), and Temporal Lobe Epilepsy with childhood Febrile Seizures (TLE-FS). Single nucleotide polymorphisms (SNPs) were selected from HapMap and dbSNP databases for the MMP-9 gene on chromosome 20. We used standard haplotype analysis and multivariate explorative analysis.

Results

There were no statistically significant associations between the analyzed SNPs in the MMP-9 gene and TLE, nor were any significant associations found with the two examined subgroups MTLE-HS and TLE-FS, confirmed by both analyses.

Conclusion

We could not identify any polymorphisms of the human MMP-9 gene that were associated with TLE, MTLE-HS or TLE-FS, in the selected SNPs. However, factors that influence MMP-9 gene expression, post-transcriptional modifications, or the balance between activation and inhibition of MMP-9 may play a role in the pathogenesis of TLE and other epileptic syndromes.

Abbreviations: ECS, extracellular space, ECM, extracellular matrix, FS, febrile seizure, HS, hippocampal sclerosis, MMP, Matrix Metalloproteinase, MMP-9, Matrix Metalloproteinase 9, MTLE, Mesial Temporal Lobe Epilepsy, MTLE-HS, Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis, TLE, Temporal Lobe Epilepsy, TLE-FS, Temporal Lobe Epilepsy with Febrile Seizures

Keywords: Association study, Hippocampal sclerosis, Matrix Metalloproteinase, MMP-9, Neuroplasticity, Temporal Lobe Epilepsy

 

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1. Introduction 

One fundamental characteristic of the human brain is its astonishing capacity to undergo life long functional and morphological changes. These processes, also collectively referred to as remodeling, include synapse formation and elimination, cortical reorganization and neurogenesis. Remodeling occurs during brain development and learning, but also serves as an adaptive mechanism to compensate for lost function.1, 2, 3 Studies of the hippocampus have disclosed a relation between synaptic remodeling and epilepsy.3, 4, 5 In Temporal Lobe Epilepsy (TLE), especially in cases with hippocampal sclerosis, remodeling may lead to defective synaptic rearrangement of neuronal circuits and thus promote epileptogenesis and disease progression.6

TLE is a serious, chronic neurological condition characterized by recurrent seizures that originate in the temporal lobe. TLE is common as it probably accounts for about one-third of all patients with epilepsy.7 A major burden for patients with this condition is the frequent resistance to pharmacotherapy, and temporal lobectomy may be required to achieve seizure control.8 There is thus an urgent need to develop new treatment strategies for this disease.

TLE is often associated with hippocampal alterations which are known to play a critical role in epileptogenesis. These alterations include sprouting of mossy fibres and aberrant formation of excitatory synapses in specific regions of the hippocampus. The underlying mechanisms of these phenomena and hence the origin of hippocampal epileptogenesis are unknown.

A recent discovery is the identification of Matrix Metalloproteinase 9 (MMP-9) as a possible key factor in the development of aberrant synaptic plasticity and dendritic pruning in TLE hippocampi.9 MMP-9 is a proteinase that cleaves extracellular matrix molecules in and around the synaptic cleft and MMP-9 activation may be an essential step in the cascade of events leading to new synapse formation. Specifically, the synaptic pool of MMP-9 could be critical for the sequence of events that underlie the development of seizures in TLE.

As transgenic rats overexpressing MMP-9 develop increased susceptibility to seizures, and deletion of the MMP-9 gene in mice leads to less severe seizures,9 we hypothesized that particular polymorphisms of the MMP-9 gene could contribute to the development of Temporal Lobe Epilepsy, or subgroups of this condition, notably Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis (MTLE-HS), and Temporal Lobe Epilepsy with childhood Febrile Seizures (TLE-FS).

In the current paper we highlight an attractive mechanistic hypothesis of the relation between TLE and MMP-9 and present an association study designed to identify possible variants of the MMP-9 gene associated with TLE or its subgroups MTLE-HS and TLE-FS.

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2. Material and methods 

2.1. Selection of subjects 

In total, 399 individuals were included in the study – 218 patients with TLE (according to the ILAE criteria, see www.ilae.org), and 181 healthy controls (without history of epilepsy or febrile seizures). Blood samples were collected between 2000 and 2004 in a cooperative project, involving seven tertiary Norwegian centers with high competence in the field of epileptology. Inclusion criteria for all individuals were: age>18 years; Caucasian race, with at least 3 of 4 grandparents of Scandinavian origin. The controls had no known familial relation to the TLE patients (typically spouse or partner). Standardized evaluation forms were used for all TLE patients and controls in addition to an overhaul of the patient records. MRI (typically 1 or 1.5T, with sagittal and axial T1, axial and coronal T2 and FLAIR) was performed in all 218 patients in order to differentiate cases with hippocampal sclerosis (MTLE-HS). We detected 56 patients with MTLE-HS and 162 cases with other TLE. 102 TLE patients were found to have had childhood febrile seizures versus 105 without. 11 patients were excluded because of unclear febrile seizure status. Written informed consent was obtained from all participating individuals and the study was approved by the regional ethical committee. The patient population is previously characterized in detail.10

2.2. Validation and characterization of SNPs 

SNP genotyping in all 218 cases and 181 controls was done using the MassARRAY system from Sequenom, www.sequenom.com (San Diego, CA, USA). A total of 40 SNPs from the MMP-9 gene on chromosome 20 were used in the assay design. The SNPs were chosen from HapMap (www.hapmap.org) and from dbSNP (www.ncbi.nlm.nih.gov/SNP). All SNPs that had a known allele frequency, in Caucasian populations, in either of these databases were included in the initial primer design. Genotype calls were assigned in real time11 based on the mass peaks present, by using the MassARRAY SpectroTYPER RT v3.4 software from Sequenom. All the results were manually inspected, using the MassARRAY TyperAnalyzer v4.0 software (Sequenom).

2.3. Analysis 1: Haploview analysis of single SNPs and haplotypes in cases versus control groups 

The HaploView 4.0 software package12 was used for defining haplotype blocks and to investigate possible associations between single SNPs and haplotypes within blocks. Criterion for block definition was as suggested by Gabriel et al.13 Both nominal p-values and p-values corrected for multiple testing have been considered. The boundary used for indicating significance was set to 5% for the single SNPs and haplotypes. Multiple corrections of the p-values were determined by repeating 10,000 random permutations of the case/control status.

2.4. Analysis 2: explorative data analysis 

Coding of data, multivariate data analysis for SNP selection and predictive modelling was used as in Heuser et al.14

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3. Results 

There were no associations between the analyzed SNPs in the MMP-9 gene and TLE, nor were any associations found with the two examined subgroups MTLE-HS and TLE-FS. Of the 40 tested SNPs, 23 were monomorphic in this material and are therefore not included in the analysis. Polymorphic SNPs included in this study are listed in Table 1, ordered by their region on chromosome 20. None of the SNPs were found to deviate from Hardy–Weinberg equilibrium.

Table 1. Polymorphic MMP-9 SNPs, ordered by region on chromosome 20.
Rs numberRegionSourceAllelesAllele frequenceChi-squarep-Value
rs391827944069902dbSNPCC/CT[205,7;170,4]0.3470.556
rs180508844071031HapMapCC/CT[195,2;165,1]0.1870.665
rs4142744544071085dbSNPAA/AG[199,2;163,0]1.6310.202
rs601772444070187dbSNPAG/GG[7,212;2,177]1.9260.165
rs391825344072918HapMapCC/CT/TT[36,96,83;22,86,63]1.6750.433
rs5578992744073006dbSNPCC/CT[211,1;174,0]0.8230.364
rs227475544073099HapMapGG/GT[172,36;129,38]1.7350.188
rs1757644073632HapMapAA/AG/GG[102,88,25;75,79,17]1.1270.569
rs223641644073982dbSNPAA/AG/GG[171,31,3;128,31,2]1.1100.574
rs610442744076255HapMapAA/GG[0,217;1,177]1.2220.269
rs227475644076518HapMapAA/AG/GG[3,35,172;2,36,131]1.3420.511
rs391826144076999HapMapAA/AG/GG[171,31,3;129,31,2]1.0560.590
rs391826244077177dbSNPAA/AG/GG[131,72,12;112,53,8]0.6350.728
rs391828244078116dbSNPAG/GG[4,207;5,167]0.4220.516
rs139254407837dbSNPAA/AG/GG[3,37,173;2,40,128]2.2450.325
rs205444407841dbSNPCC/CT/TT[36,93,83;23,87,61]2.0600.357
rs95094407856dbSNPCT/TT[10,206;7,166]0.0780.780

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4. Discussion 

4.1. Temporal Lobe Epilepsy and epileptogenesis 

TLE is of major clinical interest due to frequent resistance to pharmacotherapy and its association with hippocampal sclerosis (HS) and febrile seizures (FS). Animal models of TLE based on chemically or electrically induced seizures have disclosed major reorganization of hippocampal circuitries.15, 16, 17, 18 This reorganization includes neuronal loss, astrocyte proliferation, sprouting of mossy fibers, and aberrant formation of excitatory synapses in specific regions of the hippocampus: dentate gyrus and Ammon's horn subfield 3 (CA3). Notable changes are also found at the molecular level, including the activation of second messenger systems, immediate early genes, transcription factors, neurotrophic factors, and axon guidance molecules.19 These changes are associated with epilepsy development and progression, also known as epileptogenesis.

More specifically, the term epileptogenesis refers to the processes by which the non-epileptic brain is transformed into one that generates spontaneous seizures, and it is also used as a description of the further progression of brain tissue already capable of generating chronic, recurrent, spontaneous symptomatic- or non-symptomatic seizures.20

From a clinical point of view, TLE patients, especially those with HS, typically present with an initial precipitating incident (febrile convulsion, trauma, hypoxia, intracranial infection, etc.) in early childhood, followed by a seizure-free interval (latent or silent period). Once habitual seizures begin, they are often initially responsive to antiepileptic medication, before turning refractory. This typical disease development is likely to correlate with the biological processes that underlie epileptogenesis.21 Despite growing knowledge about the quality and quantity of hippocampal changes in TLE, the factors that precipitate such changes are still unknown.

4.2. Temporal Lobe Epilepsy and Matrix Metalloproteinase 9 

A novel approach to explaining epileptogenesis in TLE focuses on the mechanisms of plasticity and synapse formation. Specifically, this hypothesis provides a possible explanation of how recurrent and inappropriate excitatory pathways are formed in the hippocampi of TLE patients. The enzyme Matrix Metalloproteinase 9 (MMP-9) has been shown to directly affect the processes that lead to such inappropriate excitatory loops9 that in turn are thought to underlie epileptic activity. Matrix Metalloproteinases (MMPs) constitute a family of zinc dependent extracellular or membrane bound endopeptidases, subdivided according to their substrate affinities for different components of extracellular matrix. Their primary function is the cleavage of extracellular matrix (ECM) proteins and they are thus involved in processes of physiological tissue remodeling.22

MMP-9 has been implicated in various CNS pathologies including stroke,23 traumatic brain injury,24 cerebral arteriovenous malformations,25 influenza associated encephalopathy,26 systemic lupus erythematosus with CNS affection,27 and in meningitis, where it has been identified as a risk factor for developing neurological sequelae.28 In addition, recent studies have indicated a physiological role of MMP-9 in neuronal plasticity, including learning and memory as well as long-term-potentiation.29, 30 Hence, it has been suggested that MMP-9 may have an initial detrimental effect leading to neuronal cell loss but also a subsequent beneficial (restorative or neuroprotective) effect.31, 32

In relation to epilepsy, MMP-9 cleaves extracellular matrix molecules in and around the synaptic cleft, where this is thought to be a necessary step in the cascade of events leading to new synapse formation. Wilczynski et al. have examined the role of MMP-9 in TLE.9 They used two animal models of TLE in their study: exposure to the neurotoxin kainate, and to chemical kindling using pentylenetetrazole (PTZ). In studying the effect of PTZ kindling on transgenic mice with a deletion of the MMP-9 gene (MMP-9 −/−) they found that the kindled MMP-9 −/− animals developed epilepsy at a later stage and presented with less severe seizures than did the control, WT animals. Having identified this protective effect of MMP-9 gene deletion, the authors proceeded to investigate whether abundant MMP-9 would enhance epileptogenesis. They generated a transgenic (TG) rat that overexpressed neuronal MMP-9. The kindling experiment did indeed demonstrate an increased susceptibility to epileptogenesis and more severe seizures. This effect did not appear until after the first few injections, where the authors propose this is evidence to suggest the involvement of a plastic process. These results were underscored by a histological analysis showing that aberrant synaptogenesis and mossy fiber sprouting were significantly reduced in the hippocampi of MMP-9 −/− animals exposed to kainate. Overall, this experimental evidence emphasizes the role of MMP-9 as an enzyme that directly affects remodeling of synaptic linkage and that could represent a pharmacological target in epilepsy treatment.

4.3. Association study of the MMP-9 gene in a Norwegian TLE cohort 

Several lines of evidence are pointing towards an important role of genetics in TLE, such as observations of familial monogenic forms,8, 33, 34 the frequent presence of positive familial antecedents for epileptic events,35 and high association with febrile seizures.36

In the past decade, genetic association studies in epilepsy mainly focused on polymorphisms in synaptic ion channel genes, with rather unsuccessful results.37 At the same time molecular biological research provided novel candidate genes, based on recent knowledge about other possible contributors to the mechanisms of epileptogenesis, such as MMP-9. An important question is whether genetic variants of the MMP-9 gene would contribute to aberrant synaptic plasticity and formation of epileptic foci. Based on the accumulating data that indicate a role for MMP-9 in neuroplasticity and epileptogenesis, we hypothesized that particular polymorphisms of the MMP-9 gene could contribute to the development of TLE.

The validity of genetic association studies depends upon a number of factors, which have been timely reviewed in relation to research within the field of epilepsy.37 Recent guidelines for appraising genetic association studies in epilepsy might have reduced methodological failures and the amount of published association studies, but have not contributed to the disclosure of single gene associations to the common epilepsies. These guidelines were stringently adhered to in establishing the protocol for our study, reflected by the following: we used a clearly defined phenotype; we had an apparent a priori hypothesis and a strong biological plausibility. We also minimized population stratification using only Norwegian subjects with Norwegian ancestors in both case- and control group. Nevertheless, none of our analyses have shown any statistically significant association of the selected SNPs with TLE, or with the two subgroups TLE-HS or TLE-FS.

Common epilepsies are genetically complex disorders believed to be influenced by numerous susceptibility genes, and largely unknown environmental factors. Examination of selected SNPs alone does not detail the control of gene expression. In the case of MMP-9 and this study, the proposed SNP analysis does not touch upon mechanisms responsible for post-transcriptional regulation, nor the mechanisms that relate to enzyme activation and inhibition. It is also of note that once activated, MMP-9 can be inhibited by tissue inhibitors of metalloproteinases (TIMP) and by TIMP-1 in particular. While studying regulatory factors was beyond the scope of our study, they might still play a role in disrupting the mechanisms of MMP-9 secretion, transport and activation/inhibition. It would be of great interest, therefore, to assess MMP-9 activity directly in tissue resections from TLE patients. While several aspects of the role of MMP-9 in both physiological and pathophysiological states have been unraveled, there is as yet no evidence from human material that MMP-9 is involved in the development of epilepsy. Despite a relatively broad selection of SNPs in the MMP-9 gene of 218 patients, we were unable to find any association with TLE or its two subgroups. The possibility that TLE is associated with changes in MMP-9 expression or regulation cannot be ruled out and should be subject to further research.

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Acknowledgements 

We are grateful to the Norwegian GenEpA Group: Leif Gjerstad (principal investigator), Eylert Brodtkorb, Bernt Engelsen, Morten Lossius, Karl Otto Nakken, Erik Taubøll, and Erik Sætre. This study was supported by GlaxoSmithKline, The Nordic Centre of Excellence Program, and the Research Council of Norway (STORFORSK and NevroNor grants) and Polish-Norwegian Research Fund grant PNRF-96.

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PII: S1059-1311(10)00107-X

doi:10.1016/j.seizure.2010.05.003

Seizure: European Journal of Epilepsy
Volume 19, Issue 6 , Pages 335-338, July 2010

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