Enhancement of Progenitor Cell Division in the Dentate Gyrus Triggered by Initial Limbic Seizures in Rat Models of Epilepsy

Authors

  • Eiji Nakagawa,

    Corresponding author
    1. Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Shiga, Japan
    2. Department of Pediatrics, Shiga University of Medical Science, Otsu, Shiga, Japan
    3. Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia, Canada
    4. Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada
    Search for more papers by this author
  • Yoshinari Aimi,

    1. Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Shiga, Japan
    Search for more papers by this author
  • Osamu Yasuhara,

    1. Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Shiga, Japan
    Search for more papers by this author
  • Ikuo Tooyama,

    1. Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Shiga, Japan
    Search for more papers by this author
  • Morimi Shimada,

    1. Department of Pediatrics, Shiga University of Medical Science, Otsu, Shiga, Japan
    Search for more papers by this author
  • Patrick L. McGeer,

    1. Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia, Canada
    Search for more papers by this author
  • Hiroshi Kimura

    1. Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Shiga, Japan
    Search for more papers by this author

Address correspondence and reprint requests to Dr. E. Nakagawa at S-176, Division of Neurology, Department of Medicine, University Hospital-UBC site, 2211 Wesbrook Mall, Vancouver, B.C. Canada V6T 2B5. E-mail: eijin@interchange.ubc.ca

Abstract

Summary: Purpose: Mitogenic effects of seizures on granule cell progenitors in the dentate gyrus were studied in two rat models of epilepsy. We investigated which stage of epileptogenesis is critical for eliciting progenitor cell division and whether seizure-induced neuronal degeneration is responsible for the enhancement of progenitor cell division.

Methods: Seizures were induced by either kainic acid (KA) administration or electrical kindling. Neurogenesis of dentate granule cells was evaluated using the bromodeoxyuridine (BrdU) labeling method, and neuronal degeneration was assessed by in situ DNA fragmentation analysis.

Results: After injection of KA, the number of BrdU-positive granule cells began to increase at day 3 after the treatment, peaked at day 5, and returned to baseline at day 10. By day 13, the values were lower than control. After kindling, the number of BrdU-positive cells began to increase after five consecutive experiences of stage I seizures. The increase occurred from day 1 to day 3 after the last electrical stimulation, but returned to baseline by day 7. After generalized seizures were well established, repeated stimulation did not facilitate division of granule cell progenitors. DNA fragmentation was noted in pyramidal neurons in the CA1, CA3, and hilus regions at 18 h after KA injection, but not in the kindling model.

Conclusions: These observations indicate that a mechanism in epileptogenesis boosts dentate progenitor cell division, but progenitor cells may become unreactive to prolonged generalized seizures. Pyramidal neuronal degeneration is not necessary for triggering the upregulation. It is suggested that newly born granule cells may play a role in the network reorganization that occurs during epileptogenesis.

Ancillary