Abrogation of early apoptosis does not alter late inhibition of hippocampal neurogenesis after irradiation.
OBJECTIVE
Irradiation of the adult brain results in acute apoptosis of neural progenitors and vascular endothelial cells, as well as late dysfunction of neural progenitors and inhibition of neurogenesis. We sought to determine whether the early apoptotic response has a causative role in late inhibition of neurogenesis after cranial irradiation.


METHODS
Using a genetic approach with p53 and smpd1 transgenic mice and a pharmacologic approach with basic fibroblast growth factor (bFGF) to abrogate the early apoptotic response, we evaluated the late inhibition of neurogenesis in the hippocampal dentate gyrus after cranial irradiation.


RESULTS
In dentate gyrus, subgranular neural progenitors underwent p53-dependent apoptosis within 24 h after irradiation. Despite a near abrogation of neural progenitor apoptosis in p53-/- mice, the reduction in newborn neurons in dentate gyrus at 9 weeks after irradiation in p53-/- mice was not different from that observed in wildtype controls. Endothelial cell apoptosis after radiation is mediated by membrane damage initiated by activation of acid sphingomyelinase (ASMase). Deletion of the smpd1 gene (which encodes ASMase) attenuated the apoptotic response of endothelial cells. At 9 weeks after irradiation, the inhibition of hippocampal neurogenesis was not rescued by ASMase deficiency. Intravenous administration of bFGF protected both endothelial cells and neural progenitors against radiation-induced apoptosis. There was no protection against inhibition of neurogenesis at 9 weeks after irradiation in bFGF-treated mice.


CONCLUSIONS
Early apoptotic death of neural progenitors, endothelial cells, or both does not have a causative association with late inhibition of neurogenesis after irradiation.
Li
Yu-Qing
YQ
Sunnybrook Health Sciences Centre, Toronto, Canada.
Aubert
Isabelle
I
Wong
C Shun
CS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects*; D018891:Dentate Gyrus / Q000166:cytology* / Q000528:radiation effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D017353:Gene Deletion; D016158:Genes, p53; D006624:Hippocampus / Q000166:cytology / Q000528:radiation effects; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000502:physiology / Q000528:radiation effects*; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
D016222:Fibroblast Growth Factor 2; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase