Epigenetic modulation of seizure-induced neurogenesis and cognitive decline

Sebastian Jessberger, Kinichi Nakashima, Gregory D. Clemenson, Eunice Mejia, Emily Mathews, Kerstin Ure, Shiori Ogawa, Christopher M. Sinton, Fred H. Gage, Jenny Hsieh

Research output: Contribution to journalArticle

252 Scopus citations

Abstract

The conceptual understanding of hippocampal function has been challenged recently by the finding that new granule cells are born throughout life in the mammalian dentate gyrus (DG). The number of newborn neurons is dynamically regulated by a variety of factors. Kainic acid-induced seizures, a rodent model of human temporal lobe epilepsy, strongly induce the proliferation of DG neurogenic progenitor cells and are also associated with long-term cognitive impairment. We show here that the antiepileptic drug valproic acid (VPA) potently blocked seizure-induced neurogenesis, an effect that appeared to be mainly mediated by inhibiting histone deacetylases (HDAC) and normalizing HDAC-dependent gene expression within the epileptic dentate area. Strikingly, the inhibition of aberrant neurogenesis protected the animals from seizure-induced cognitive impairment in a hippocampus-dependent learning task.Wepropose that seizure-generated granule cells have the potential to interfere with hippocampal function and contribute to cognitive impairment caused by epileptic activity within the hippocampal circuitry. Furthermore, our data indicate that the effectiveness of VPA as an antiepileptic drug may be partially explained by the HDAC-dependent inhibition of aberrant neurogenesis induced by seizure activity within the adult hippocampus.

Original languageEnglish (US)
Pages (from-to)5967-5975
Number of pages9
JournalJournal of Neuroscience
Volume27
Issue number22
DOIs
StatePublished - May 30 2007

Keywords

  • Hippocampus
  • Histone deacetylase
  • Learning
  • Neurogenesis
  • Object recognition
  • Seizure
  • Valproic acid

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Jessberger, S., Nakashima, K., Clemenson, G. D., Mejia, E., Mathews, E., Ure, K., Ogawa, S., Sinton, C. M., Gage, F. H., & Hsieh, J. (2007). Epigenetic modulation of seizure-induced neurogenesis and cognitive decline. Journal of Neuroscience, 27(22), 5967-5975. https://doi.org/10.1523/JNEUROSCI.0110-07.2007