Aberrant seizure-induced neurogenesis in experimental temporal lobe epilepsy.
Neurogenesis in the hippocampal dentate gyrus persists throughout life and is increased by seizures. The dentate granule cell (DGC) layer is often abnormal in human and experimental temporal lobe epilepsy, with dispersion of the layer and the appearance of ectopic granule neurons in the hilus. We tested the hypothesis that these abnormalities result from aberrant DGC neurogenesis after seizure-induced injury. Bromodeoxyuridine labeling, in situ hybridization, and immunohistochemistry were used to identify proliferating progenitors and mature DGCs in the adult rat pilocarpine temporal lobe epilepsy model. We also examined dentate gyri from epileptic human hippocampal surgical specimens. Prox-1 immunohistochemistry and pulse-chase bromodeoxyuridine labeling showed that progenitors migrate aberrantly to the hilus and molecular layer after prolonged seizures and differentiate into ectopic DGCs in rat. Neuroblast marker expression indicated the delayed appearance of chainlike progenitor cell formations extending into the hilus and molecular layer, suggesting that seizures alter migratory behavior of DGC precursors. Ectopic putative DGCs also were found in the hilus and molecular layer of epileptic human dentate gyrus. These findings indicate that seizure-induced abnormalities of neuroblast migration lead to abnormal integration of newborn DGCs in the epileptic adult hippocampus, and implicate aberrant neurogenesis in the development or progression of recurrent seizures.
Parent
Jack M
JM
Department of Neurology, University of Michigan Medical Center, 4412 Kresge III, 200 Zina Pitcher Place, Ann Arbor, MI 48109-0585, USA. parent@umich.edu
Elliott
Robert C
RC
Pleasure
Samuel J
SJ
Barbaro
Nicholas M
NM
Lowenstein
Daniel H
DH
D000328:Adult; D000818:Animals; D000963:Antimetabolites / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism* / Q000503:physiopathology; D006624:Hippocampus / Q000002:abnormalities* / Q000166:cytology / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D018721:Muscarinic Agonists / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010862:Pilocarpine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000502:physiology; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein
D000963:Antimetabolites; D015415:Biomarkers; D018398:Homeodomain Proteins; D018721:Muscarinic Agonists; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D010862:Pilocarpine; D001973:Bromodeoxyuridine