Acute neonatal glucocorticoid exposure produces selective and rapid cerebellar neural progenitor cell apoptotic death

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.

Identification of select glucocorticoids as Smoothened agonists: Potential utility for regenerative medicine

“…6). No such growth-enabling responses were observed in GCPs treated with cortisone, dexamethasone, prednisolone, or corticosterone, observations consistent with recent reports (25)(26)(27) (Fig. 6).…”

“…Other glucocorticoids, including dexamethasone, prednisone, cortisone, and corticosterone, are used to treat premature infants and have been observed to cause neuronal apoptosis and to inhibit neuronal precursors of the cerebellar granule neuronal lineage in a mouse model (25,26). On the basis that Shh exposure cannot overcome the effects of dexamethasone but can antagonize the effects of hydrocortisone, Heine and Rowitch (25) recommend that hydrocortisone be used as a replacement for dexamethasone in infants because of the reduced potential for neurotoxicity.…”

Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11βHSD2-dependent mechanism

“…11βHSD2 is expressed in the developing CNS, including in cerebellar granule neuron precursors (CGNPs) (9), where its function is necessary for normal cerebellar development (10). Animal studies reveal that antenatal and neonatal exposure to supraphysiologic levels of GCs, analogous to treatments in humans, results in delayed and/or abnormal development of the cerebellum (11) and increased apoptosis of CGNPs (12), indicating that the cerebellum is a suitable model system to study adverse effects of GCs on brain development.…”

Clonal analysis reveals granule cell behaviors and compartmentalization that determine the folded morphology of the cerebellum

“…An increase or decrease in the production of gcs results in a corresponding change in the size of folia (Altman et al, 1969;Bohn and Lauder, 1980;Corrales et al, 2006;Lewis et al, 2004;Noguchi et al, 2008). Gcs are generated by a unique germinal zone termed the external gc layer (EGL), which covers the surface of the mouse Cb from embryonic day (E) 15.5 to postnatal day (P) 16 (Altman and Bayer, 1997;Sillitoe and Joyner, 2007;Sudarov and Joyner, 2007).…”