Molecular alterations in areas generating fast ripples in an animal model of temporal lobe epilepsy

Kellen D Winden; Anatol Bragin; Jerome Engel; Dan H Geschwind

doi:10.1016/j.nbd.2015.02.011

Molecular alterations in areas generating fast ripples in an animal model of temporal lobe epilepsy

Neurobiol Dis. 2015 Jun:78:35-44. doi: 10.1016/j.nbd.2015.02.011. Epub 2015 Mar 25.

Authors

Kellen D Winden¹, Anatol Bragin², Jerome Engel³, Dan H Geschwind⁴

Affiliations

¹ Interdepartmental Program for Neuroscience, University of California, Los Angeles, Los Angeles, CA, USA; Program in Neurogenetics, University of California, Los Angeles, Los Angeles, CA, USA; Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA.
² Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA; The Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA; Department of Neurobiology, University of California, Los Angeles, Los Angeles, CA, USA; The Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA; Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Interdepartmental Program for Neuroscience, University of California, Los Angeles, Los Angeles, CA, USA; Program in Neurogenetics, University of California, Los Angeles, Los Angeles, CA, USA; Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA; Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: dhg@mednet.ucla.edu.

Abstract

The molecular basis of epileptogenesis is poorly characterized. Studies in humans and animal models have identified an electrophysiological signature that precedes the onset of epilepsy, which has been termed fast ripples (FRs) based on its frequency. Multiple lines of evidence implicate regions generating FRs in epileptogenesis, and FRs appear to demarcate the seizure onset zone, suggesting a role in ictogenesis as well. We performed gene expression analysis comparing areas of the dentate gyrus that generate FRs to those that do not generate FRs in a well-characterized rat model of epilepsy. We identified a small cohort of genes that are differentially expressed in FR versus non-FR brain tissue and used quantitative PCR to validate some of those that modulate neuronal excitability. Gene expression network analysis demonstrated conservation of gene co-expression between non-FR and FR samples, but examination of gene connectivity revealed changes that were most pronounced in the cm-40 module, which contains several genes associated with synaptic function and the differentially expressed genes Kcna4, Kcnv1, and Npy1r that are down-regulated in FRs. We then demonstrate that the genes within the cm-40 module are regulated by seizure activity and enriched for the targets of the RNA binding protein Elavl4. Our data suggest that seizure activity induces co-expression of genes associated with synaptic transmission and that this pattern is attenuated in areas displaying FRs, implicating the failure of this mechanism in the generation of FRs.

Keywords: Coexpression network analysis; Epilepsy; Fast ripples; Microarray.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Dentate Gyrus / physiopathology*
Disease Models, Animal
Epilepsy, Temporal Lobe / genetics*
Epilepsy, Temporal Lobe / physiopathology*
Gene Expression
Gene Regulatory Networks
Rats

Abstract

Publication types

MeSH terms

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