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Cited by 76Epilepsy research and treatmentNeuroscience and Neuropharmacology ResearchPharmacological Effects and Toxicity Studies

A Systems Level, Functional Genomics Analysis of Chronic Epilepsy

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Winden, Kellen D., Karsten, Stanislav L., Bragin, Anatol, Kudo, Lili C., Gehman, Lauren, Ruidera, Josephine, Geschwind, Daniel H., Engel, Jerome·2011·PLoS ONE
DOI 10.1371/journal.pone.0020763PMC PMC3114768
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Abstract

Neither the molecular basis of the pathologic tendency of neuronal circuits to generate spontaneous seizures (epileptogenicity) nor anti-epileptogenic mechanisms that maintain a seizure-free state are well understood. Here, we performed transcriptomic analysis in the intrahippocampal kainate model of temporal lobe epilepsy in rats using both Agilent and Codelink microarray platforms to characterize the epileptic processes. The experimental design allowed subtraction of the confounding effects of the lesion, identification of expression changes associated with epileptogenicity, and genes upregulated by seizures with potential homeostatic anti-epileptogenic effects. Using differential expression analysis, we identified several hundred expression changes in chronic epilepsy, including candidate genes associated with epileptogenicity such as Bdnf and Kcnj13. To analyze these data from a systems perspective, we applied weighted gene co-expression network analysis (WGCNA) to identify groups of co-expressed genes (modules) and their central (hub) genes. One such module contained genes upregulated in the epileptogenic region, including multiple epileptogenicity candidate genes, and was found to be involved the protection of glial cells against oxidative stress, implicating glial oxidative stress in epileptogenicity. Another distinct module corresponded to the effects of chronic seizures and represented changes in neuronal synaptic vesicle trafficking. We found that the network structure and connectivity of one hub gene, Sv2a, showed significant changes between normal and epileptogenic tissue, becoming more highly connected in epileptic brain. Since Sv2a is a target of the antiepileptic levetiracetam, this module may be important in controlling seizure activity. Bioinformatic analysis of this module also revealed a potential mechanism for the observed transcriptional changes via generation of longer alternatively polyadenlyated transcripts through the upregulation of the RNA binding protein HuD. In summary, combining conventional statistical methods and network analysis allowed us to interpret the differentially regulated genes from a systems perspective, yielding new insight into several biological pathways underlying homeostatic anti-epileptogenic effects and epileptogenicity.

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  • HuD protein levels, as well as a cohort of its target mRNAs such as GAP-43, CAMKIIα and Homer, increase in several brain regions including the dentate gyrus (DG) following neurotoxin-induced seizure.

    “In parallel with this potential role, studies have demonstrated that HuD protein levels, as well as a cohort of its target mRNAs such as GAP-43, CAMKIIα and Homer, increase in several brain regions including the dentate gyrus (DG) following neurotoxin-induced seizure (Bolognani et al. 2007a; Tiruchinapalli et al. 2008a; Winden et al. 2011).”

    From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Winden et al. 2011

    The Results (‘Mechanisms of neuronal response to seizures’; page not available) report increased HuD expression by qRT-PCR in both hemispheres of animals with chronic seizures and an association between HuD target genes and seizures. The paper uses a kainic-acid seizure model focused on the hippocampus and dentate gyrus, but these passages do not establish increased HuD protein levels, increases in the named target mRNAs, or increases across several brain regions. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • Kainic acid-induced seizures in rats increase HuD and several of its target mRNAs.

    “A third study assessed gene expression using microarray platforms to show that HuD and several of its target mRNAs increased following kainic acid-induced seizures in rats (Winden et al. 2011).”

    From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Winden et al. 2011

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References 78 · Cited by 76

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Authors
Winden, K. D., Karsten, S. L., Bragin, A., Kudo, L. C., Gehman, L., Ruidera, J., Geschwind, D. H., & Engel, J.
Affiliations
University of California, Los Angeles (US)
Corresponding author
  • Geschwind, Daniel H.
  • Engel, Jerome
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2011-06-14
Volume
6
Issue
6
Pages
e20763
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0020763
PMC
PMC3114768
OpenAlex
W2049963231
Cited by
76
References
78
Citations by year
2025: 3 · 2024: 6 · 2023: 2 · 2022: 5 · 2021: 4 · 2020: 4 · 2019: 3 · 2018: 3 · 2017: 4 · 2016: 4 · 2015: 8 · 2014: 7 · 2013: 13 · 2012: 5
FWCI
6.60
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Institutes of Health
  • National Institute of Mental Health (T32MH073526)
  • National Institute of General Medical Sciences (GM-08042, T32GM008042)
  • National Institute of Neurological Disorders and Stroke (R37NS033310)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
Keywords
chronic epilepsy, epileptogenicity, temporal lobe epilepsy, gene expression profiling, weighted gene co-expression network analysis, hub genes, synaptic vesicle trafficking, SV2A, levetiracetam, alternative polyadenylation, HUD, brain-derived neurotrophic factor, KCNJ13
MeSH terms
Animals, Chronic Disease, Disease Models, Animal, Epilepsy, Male, Neurons, Phenotype, Seizures, Synaptic Vesicles, Transcription, Genetic, Up-Regulation, Genome, Rats, Wistar, Oxidative Stress, Gene Expression Profiling, Genomics, Systems Biology, Rats, Gene Regulatory Networks, Genetic Association Studies, Molecular Sequence Annotation

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