Abstract
There has been a growing controversy regarding the continued use of glucocorticoid therapy to treat respiratory dysfunction associated with prematurity, as mounting clinical evidence has shown neonatal exposure produces permanent neuromotor and cognitive deficits. Here we report that, during a selective neonatal window of vulnerability, a single glucocorticoid injection in the mouse produces rapid and selective apoptotic cell death of the proliferating neural progenitor cells in the cerebellar external granule layer and permanent reductions in neuronal cell counts of their progeny, the cerebellar internal granule layer neurons. Our estimates suggest that this mouse window of vulnerability would correspond in the human to a period extending from approximately 20 weeks gestation to 6.5 weeks after birth. This death pathway is critically regulated by the proapoptotic Bcl-2 family member Puma and is independent of p53 expression. These rodent data indicate that there exists a previously unknown window of vulnerability during which a single glucocorticoid exposure at clinically relevant doses can produce neural progenitor cell apoptosis and permanent cerebellar pathology that may be responsible for some of the iatrogenically induced neurodevelopmental abnormalities seen in children exposed to this drug. This vulnerability may be related to the physiological role of glucocorticoids in regulating programmed cell death in the mammalian cerebellum.
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Abbreviations
- ANOVA:
-
analysis of variance
- AraC:
-
cytosine arabinoside
- C3A:
-
activated caspase-3
- DEX:
-
dexamethasone
- EGL:
-
external granule layer
- GC:
-
glucocorticoid
- KO:
-
knockout
- NPC:
-
neural progenitor cell
- PND:
-
postnatal day
- WT:
-
wild type
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Acknowledgements
KCW and KAR thank UAB Neuroscience Core Facilities (NS47466 and NS57098) for technical support. KAR and KCW are supported by NIH grants NS35107 and NS41962. Puma −/− mice were generously provided to us by Dr. Andreas Strasser (University of Melbourne). KKN, NBF, and JWO thank D Smith and H Wang for technical assistance. KKN is supported by NIH grants DA07261, DA05072, and HD055365. DFW is supported by an NIH P30 Neuroscience Blueprint Core Grant NS057105. NBF is supported by NIH grant ES12443 and HD055365. JWO is supported by NIH grant DA05072 and HD055365. Finally, we thank K Dikranian and A Parsadanian for advice and technical support with double immunofluorescent histology.
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Noguchi, K., Walls, K., Wozniak, D. et al. Acute neonatal glucocorticoid exposure produces selective and rapid cerebellar neural progenitor cell apoptotic death. Cell Death Differ 15, 1582–1592 (2008). https://doi.org/10.1038/cdd.2008.97
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DOI: https://doi.org/10.1038/cdd.2008.97
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