Seizures induce proliferation and dispersion of doublecortin-positive hippocampal progenitor cells

Exp Neurol. 2005 Dec;196(2):342-51. doi: 10.1016/j.expneurol.2005.08.010. Epub 2005 Oct 5.

Abstract

One neuropathological hallmark of temporal lobe epilepsy is granule cell dispersion, a widening of the hippocampal granule cell layer (GCL) with abnormally positioned excitatory neurons. The finding that seizure activity also induces adult hippocampal neurogenesis was taken largely as indicative of a regenerative attempt, not as part of the pathology. The aim of our study was to characterize a potential relationship between granule cell dispersion and seizure-induced neurogenesis. Kainic acid (KA)-induced seizures in mice led to increased cell proliferation and new neurons persisted for months after the seizures. We show that the proliferative stimulus did not affect nestin-expressing early precursor cells that primarily respond to physiologic mitogenic stimuli, but stimulated the division of late type-3 progenitor cells, which express doublecortin (DCX), a protein associated with cell migration. This delayed proliferation presumably interfered with migration, leading to a significant dispersion of DCX-positive progenitors and early postmitotic neurons within the dentate gyrus granule cell layer. We propose that initial seizures induce ectopic precursor cell proliferation resulting in the dispersion of immature neurons within the adult granule cell layer. Thus, seizure-generated neurons might contribute to the disease process of epilepsy.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Bromodeoxyuridine / metabolism
  • Calbindin 2
  • Cell Count
  • Cell Division / drug effects
  • Cell Movement / drug effects
  • Cell Movement / physiology*
  • Cell Proliferation* / drug effects
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation / drug effects
  • Glial Fibrillary Acidic Protein / metabolism
  • Green Fluorescent Proteins / biosynthesis
  • Hippocampus / pathology*
  • Immunohistochemistry / methods
  • Intermediate Filament Proteins / genetics
  • Intermediate Filament Proteins / metabolism
  • Kainic Acid
  • Ki-67 Antigen / metabolism
  • Mice
  • Mice, Transgenic
  • Microtubule-Associated Proteins / metabolism*
  • Models, Biological
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Nestin
  • Neuropeptides / metabolism*
  • Phosphopyruvate Hydratase / metabolism
  • S100 Calcium Binding Protein G / metabolism
  • Seizures / chemically induced
  • Seizures / metabolism*
  • Seizures / pathology
  • Stem Cells / metabolism*
  • Stem Cells / pathology
  • Time Factors

Substances

  • Calbindin 2
  • Glial Fibrillary Acidic Protein
  • Intermediate Filament Proteins
  • Ki-67 Antigen
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Nes protein, mouse
  • Nestin
  • Neuropeptides
  • S100 Calcium Binding Protein G
  • doublecortin protein
  • Green Fluorescent Proteins
  • Phosphopyruvate Hydratase
  • Bromodeoxyuridine
  • Kainic Acid