Glial responses during epileptogenesis in Mus musculus point to potential therapeutic targets

PLoS One. 2018 Aug 16;13(8):e0201742. doi: 10.1371/journal.pone.0201742. eCollection 2018.

Abstract

The Mesio-Temporal Lobe Epilepsy syndrome is the most common form of intractable epilepsy. It is characterized by recurrence of focal seizures and is often associated with hippocampal sclerosis and drug resistance. We aimed to characterize the molecular changes occurring during the initial stages of epileptogenesis in search of new therapeutic targets for Mesio-Temporal Lobe Epilepsy. We used a mouse model obtained by intra-hippocampal microinjection of kainate and performed hippocampal whole genome expression analysis at 6h, 12h and 24h post-injection, followed by multilevel bioinformatics analysis. We report significant changes in immune and inflammatory responses, neuronal network reorganization processes and glial functions, predominantly initiated during status epilepticus at 12h and persistent after the end of status epilepticus at 24h post-kainate. Upstream regulator analysis highlighted Cyba, Cybb and Vim as central regulators of multiple overexpressed genes implicated in glial responses at 24h. In silico microRNA analysis indicated that miR-9, miR-19b, miR-129, and miR-223 may regulate the expression of glial-associated genes at 24h. Our data support the hypothesis that glial-mediated inflammatory response holds a key role during epileptogenesis, and that microglial cells may participate in the initial process of epileptogenesis through increased ROS production via the NOX complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticonvulsants / pharmacology*
  • Cell Death / drug effects
  • Computational Biology
  • Computer Simulation
  • Disease Models, Animal
  • Epilepsy, Temporal Lobe / drug therapy*
  • Epilepsy, Temporal Lobe / immunology
  • Gene Expression Regulation / drug effects
  • Hippocampus / drug effects
  • Hippocampus / immunology
  • Kainic Acid
  • Male
  • Mice, Inbred C57BL
  • MicroRNAs / metabolism
  • Neuroglia / drug effects*
  • Neuroglia / immunology
  • Status Epilepticus / drug therapy*
  • Status Epilepticus / immunology

Substances

  • Anticonvulsants
  • MicroRNAs
  • Kainic Acid

Grant support

Research funding was provided by INSERM and from the European Union 6th Framework Program for Research and Technological Development, "Life sciences, genomics and biotechnology for health", VALAPODYN, contract # LSHG-CT-2006-037277. This work was also supported by geneXplain GmbH (http://genexplain.com/). The funder provided support in the form of salaries for author OK-M, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section.