Status epilepticus during old age is not associated with enhanced hippocampal neurogenesis

Authors

  • Muddanna S. Rao,

    1. Medical Research & Surgery Services, Veterans Affairs Medical Center, Durham NC 27705
    2. Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham NC 27710
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    • Muddanna S. Rao and Bharathi Hattiangady contributed equally to this work.

  • Bharathi Hattiangady,

    1. Medical Research & Surgery Services, Veterans Affairs Medical Center, Durham NC 27705
    2. Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham NC 27710
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    • Muddanna S. Rao and Bharathi Hattiangady contributed equally to this work.

  • Ashok K. Shetty

    Corresponding author
    1. Medical Research & Surgery Services, Veterans Affairs Medical Center, Durham NC 27705
    2. Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham NC 27710
    • Division of Neurosurgery, DUMC Box 3807, Duke University Medical Center, Durham NC 27710, USA
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Abstract

Increased production of new neurons in the adult dentate gyrus (DG) by neural stem/progenitor cells (NSCs) following acute seizures or status epilepticus (SE) is a well known phenomenon. However, it is unknown whether NSCs in the aged DG have similar ability to upregulate neurogenesis in response to SE. We examined DG neurogenesis after the induction of continuous stages III-V seizures (SE) for over 4 h in both young adult (5-months old) and aged (24-months old) F344 rats. The seizures were induced through 2–4 graded intraperitoneal injections of the excitotoxin kainic acid (KA). Newly born cells in the DG were labeled via daily intraperitoneal injections of the 5′-bromodeoxyuridine (BrdU) for 12 days, which commenced shortly after the induction of SE in KA-treated rats. New cells and neurons in the subgranular zone (SGZ) and the granule cell layer (GCL) were analyzed at 24 h after the last BrdU injection using BrdU and doublecortin (DCX) immunostaining, BrdU-DCX and BrdU-NeuN dual immunofluorescence and confocal microscopy, and stereological cell counting. Status epilepticus enhanced the numbers of newly born cells (BrdU+ cells) and neurons (DCX+ neurons) in young adult rats. In contrast, similar seizures in aged rats, though greatly increased the number of newly born cells in the SGZ/GCL, failed to increase neurogenesis due to a greatly declined neuronal fate-choice decision of newly born cells. Only 9% of newly born cells in the SGZ/GCL differentiated into neurons in aged rats that underwent SE, in comparison to the 76% neuronal differentiation observed in age-matched control rats. Moreover, the number of newly born cells that migrate abnormally into the dentate hilus (i.e., ectopic granule cells) after SE in the aged hippocampus is 92% less than that observed in the young adult hippocampus after similar SE. Thus, SE fails to increase the addition of new granule cells to the GCL in the aged DG, despite a considerable upregulation in the production of new cells, and SE during old age leads to much fewer ectopic granule cells. These results have clinical relevance because earlier studies have implied that both increased and abnormal neurogenesis occurring after SE in young animals contributes to chronic epilepsy development. © 2008 Wiley-Liss, Inc.

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