Seizures induce proliferation and dispersion of doublecortin-positive hippocampal progenitor cells.
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.
Jessberger
Sebastian
S
VolkswagenStiftung Research Group at the Department of Experimental Neurology, Charité University Medicine, Berlin, Germany.
Römer
Benedikt
B
Babu
Harish
H
Kempermann
Gerd
G
D000704:Analysis of Variance; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D064032:Calbindin 2; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D006624:Hippocampus / Q000473:pathology*; D007150:Immunohistochemistry / Q000379:methods; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D007608:Kainic Acid; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D009479:Neuropeptides / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
D064032:Calbindin 2; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; D019394:Ki-67 Antigen; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D009479:Neuropeptides; D064030:S100 Calcium Binding Protein G; D049452:Green Fluorescent Proteins; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine; D007608:Kainic Acid