Large-scale expression study of human mesial temporal lobe epilepsy: evidence for dysregulation of the neurotransmission and complement systems in the entorhinal cortex

Jamali, Sarah; Bartolomei, Fabricē; Robaglia-Schlupp, Andrée; Massacrier, Annick; Péragut, Jean-Claude; Régis, Jean; Dufour, H.; Ravid, Rivka; Roll, Patrice; Pereira, Sandrine; Royer, Barbara; Roëckel-Trevisiol, Nathalie; Fontaine, Marc; Guye, Maxime; Boucraut, José; Chauvel, Patrick; Cau, Pierre; Szepetowski, Pierre

doi:10.1093/brain/awl001

Cited by 96 publications

(85 citation statements)

References 87 publications

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“…Their further investigation as potential early markers for the human syndrome is warranted. In other microarray studies of human MTLE samples, Serotransferrin and Tenancin were upregulated while Amphiphysin was downregulated, in good accordance with our data 12,92,93 .…”

Section: Validation Of Findings In Other Studies Of Human/mouse Mtle supporting

confidence: 91%

High-Throughput LC–MS/MS Proteomic Analysis of a Mouse Model of Mesiotemporal Lobe Epilepsy Predicts Microglial Activation Underlying Disease Development

Bitsika

Duveau²,

Simon-Areces

et al. 2016

J. Proteome Res.

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Uncovering the molecular mechanisms of Mesial temporal lobe epilepsy (MTLE) is critical to identify therapeutic targets. In this study, we performed global protein expression analysis of a kainic acid (KA) MTLE mouse model at various time-points (1d, 3d, 30d post KA injection -dpi), representing specific stages of the syndrome.High resolution liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), in combination to label-free protein quantification, using three processing approaches for quantification, was applied. Following comparison of KA versus NaCl-injected mice, 22, 53 and 175 proteins were differentially (statistically significant) expressed at 1, 3 and 30dpi respectively, according to all 3 quantification approaches. Selected findings were confirmed by multiple reaction monitoring LC-MS/MS. As a positive control, the astrocyte marker GFAP was found to be upregulated (3dpi:1.9 fold; 30dpi:12.5 fold), also verified by IHC. The results collectively suggest that impairment in synaptic transmission occurs even right after initial status epilepticus (1dpi), with neurodegeneration becoming more extensive during epileptogenesis (3dpi) and sustained at the chronic phase (30dpi), where also extensive glial and astrocyte-mediated inflammation is evident. This molecular profile is in line with observed phenotypic changes in human MTLE, providing the basis for future studies on new molecular targets for the disease.

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Section: Validation Of Findings In Other Studies Of Human/mouse Mtle supporting

confidence: 91%

High-Throughput LC–MS/MS Proteomic Analysis of a Mouse Model of Mesiotemporal Lobe Epilepsy Predicts Microglial Activation Underlying Disease Development

Bitsika

Duveau²,

Simon-Areces

et al. 2016

J. Proteome Res.

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“…The significance of microarray-identified genes regulated by preconditioning not validated by rtPCR should be viewed with caution. This level of agreement between the techniques compares well to other epilepsy and tolerance microarray studies (Stenzel-Poore et al, 2003;Hunsberger et al, 2005;Jamali et al, 2006). It also underlines the need for validation of a subset of genes or genes upon which future research may be directed, which was not undertaken in a recent study on epileptic preconditioning (Borges et al, 2007).…”

Section: Discussionsupporting

confidence: 68%

Microarray profile of seizure damage-refractory hippocampal CA3 in a mouse model of epileptic preconditioning

et al. 2007

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A neuroprotected state can be acquired by preconditioning brain with a stimulus that is subthreshold for damage (tolerance). Acquisition of tolerance involves coordinate, bi-directional changes to gene expression levels and the re-programmed phenotype is determined by the preconditioning stimulus. While best studied in ischemic brain there is evidence brief seizures can confer tolerance against prolonged seizures (status epilepticus). Presently, we developed a model of epileptic preconditioning in mice and used microarrays to gain insight into the transcriptional phenotype within the target hippocampus at the time tolerance had been acquired. Epileptic tolerance was induced by an episode of non-damaging seizures in adult C57Bl/6 mice using a systemic injection of kainic acid. Neuron and DNA damage-positive cell counts 24 h after status epilepticus induced by intraamygdala microinjection of kainic acid revealed preconditioning given 24 h prior reduced CA3 neuronal death by ~45% compared with non-tolerant seizure mice. Microarray analysis of over 39,000 transcripts (Affymetrix 430 2.0 chip) from microdissected CA3 subfields was undertaken at the point at which tolerance was acquired. Results revealed a unique profile of small numbers of equivalently up-and down-regulated genes with biological functions that included transport and localization, ubiquitin metabolism, apoptosis and cell cycle control. Select microarray findings were validated post hoc by real-time polymerase chain reaction and Western blotting. The present study defines a paradigm for inducing epileptic preconditioning in mice and first insight into the global transcriptome of the seizure-damage refractory brain. Keywordsepilepsy; transcriptome; kainic acid; tolerance; neuroprotection; apoptosis Stressful and potentially noxious insults that are subthreshold for damage are capable of rendering brain refractory to damage incurred by a subsequent, prolonged and otherwise harmful stressor (Dirnagl et al., 2003). This process, termed preconditioning, is a highly conserved endogenous mechanism by which brain can protect itself (tolerance) (Chen and Simon, 1997 Tolerance in brain was originally identified as a gene synthesis-dependent process that took 1-3 days to be acquired in vivo (Kitagawa et al., 1991;Simon et al., 1993;Chen et al., 1996). The process is highly conserved, being readily elicited in numerous rat and mouse models of ischemic brain injury (Dirnagl et al., 2003;Gidday, 2006;Stenzel-Poore et al., 2007). It may also have clinical relevance as evinced by more favorable outcomes in patients experiencing transient ischemic attacks prior to a large stroke (Weih et al., 1999). Preconditioning can also be induced by other brain insults including seizure (Sasahira et al., 1995;Najm et al., 1998;El Bahh et al., 2001;Borges et al., 2007) and certain chemicals/drugs (Rosenzweig et al., 2004), and cross-tolerance whereby ischemic and other paradigms are combined has also been reported in rodents (Plamondon et al., 1999;Towfighi et al., 1999).Mi...

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“…Interestingly, sequential infusion of individual proteins of the membrane attack pathway into the hippocampus of freely moving rats induces seizures as well as cytotoxicity (Xiong et al, 2003). A recent microarray study on entorhinal cortex material of MTLE patients also has pointed to the involvement of complement activation (Jamali et al, 2006). The changes in the immune response, the activation of proinflammatory cytokines and associated processes found in our model may be related to the breakdown of the BBB that occurs directly after SE .…”

Section: Discussionmentioning

confidence: 56%

Potential New Antiepileptogenic Targets Indicated by Microarray Analysis in a Rat Model for Temporal Lobe Epilepsy

Gorter¹,

Vliet²,

Aronica³

et al. 2006

J. Neurosci.

298

243

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. A group that was stimulated but that had not experienced SE and later epilepsy was also included (group nS). Gene expression analysis was performed using the Affymetrix Gene Chip System (RAE230A). We used GENMAPP and Gene Ontology to identify global biological trends in gene expression data. The immune response was the most prominent process changed during all three phases of epileptogenesis. Synaptic transmission was a downregulated process during the acute and latent phases. GABA receptor subunits involved in tonic inhibition were persistently downregulated. These changes were observed mostly in both CA3 and EC but not in CB. Rats that were stimulated but that did not develop spontaneous seizures later on had also some changes in gene expression, but this was not reflected in a significant change of a biological process. These data suggest that the targeting of specific genes that are involved in these biological processes may be a promising strategy to slow down or prevent the progression of epilepsy. Especially genes related to the immune response, such as complement factors, interleukins, and genes related to prostaglandin synthesis and coagulation pathway may be interesting targets.

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Large-scale expression study of human mesial temporal lobe epilepsy: evidence for dysregulation of the neurotransmission and complement systems in the entorhinal cortex

Cited by 96 publications

References 87 publications

High-Throughput LC–MS/MS Proteomic Analysis of a Mouse Model of Mesiotemporal Lobe Epilepsy Predicts Microglial Activation Underlying Disease Development

High-Throughput LC–MS/MS Proteomic Analysis of a Mouse Model of Mesiotemporal Lobe Epilepsy Predicts Microglial Activation Underlying Disease Development

Microarray profile of seizure damage-refractory hippocampal CA3 in a mouse model of epileptic preconditioning

Potential New Antiepileptogenic Targets Indicated by Microarray Analysis in a Rat Model for Temporal Lobe Epilepsy

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