Sonic Hedgehog Agonist Protects Against Complex Neonatal Cerebellar Injury

Abstract

The cerebellum undergoes rapid growth during the third trimester and is vulnerable to injury and deficient growth in infants born prematurely. Factors associated with preterm cerebellar hypoplasia include chronic lung disease and postnatal glucocorticoid administration. We modeled chronic hypoxemia and glucocorticoid administration in neonatal mice to study whole cerebellar and cell type-specific effects of dual exposure. Chronic neonatal hypoxia resulted in permanent cerebellar hypoplasia. This was compounded by administration of prednisolone as shown by greater volume loss and Purkinje cell death. In the setting of hypoxia and prednisolone, administration of a small molecule Smoothened-Hedgehog agonist (SAG) preserved cerebellar volume and protected against Purkinje cell death. Such protective effects were observed even when SAG was given as a one-time dose after dual insult. To model complex injury and determine cell type-specific roles for the hypoxia inducible factor (HIF) pathway, we performed conditional knockout of von Hippel Lindau (VHL) to hyperactivate HIF1α in cerebellar granule neuron precursors (CGNP) or Purkinje cells. Surprisingly, HIF activation in either cell type resulted in no cerebellar deficit. However, in mice administered prednisolone, HIF overactivation in CGNPs resulted in significant cerebellar hypoplasia, whereas HIF overactivation in Purkinje cells caused cell death. Together, these findings indicate that HIF primes both cell types for injury via glucocorticoids, and that hypoxia/HIF + postnatal glucocorticoid administration act on distinct cellular pathways to cause cerebellar injury. They further suggest that SAG is neuroprotective in the setting of complex neonatal cerebellar injury.Electronic supplementary materialThe online version of this article (10.1007/s12311-017-0895-0) contains supplementary material, which is available to authorized users.

Emerging connections between cerebellar development, behaviour and complex brain disorders

“…On a larger scale, the onset of Shh signaling correlates with the formation of fissures, contributing to macro-level features of cerebellar morphology, since the regulation of GC number and orientation is a key factor controlling this process 32 . As the temporal range of Shh signaling is considerably wide, spanning the perinatal period, studies using mouse models of neonatal injury suggest that disruption of Shh signaling is related to morphological and structural abnormalities in the cerebellum 33 . In humans, studies from autopsy tissue indicates that premature birth is correlated to decreased Shh expression in PCs, along with decreased EGL and IGL thickness 34 .…”

Oxygen Tension and the VHL-Hif1α Pathway Determine Onset of Neuronal Polarization and Cerebellar Germinal Zone Exit

“…Thus, the Pard complex not only regulates adhesive affinities to post-mitotic neurons or glial during GZ exit and migration but also promotes an O 2 -tension-dependent loosening of GNP adhesion to GZ niche ECM promoting GZ occupancy. Interestingly, Hif1a and Itgb1 loss of function both reduce GNP sensitivity to mitogen signaling (Blaess et al, 2004;Nguyen et al, 2018), suggesting that investigation of the O 2 -tension-cell-polarity-ECM interactions will yield insights into not only how these interactions maintain appropriate levels of neuronal differentiation but also how O 2 shapes neuronal circuit formation.…”

Cerebellum and Prematurity: A Complex Interplay Between Disruptive and Dysmaturational Events

“…Conversely, the interplay between SHH and glucocorticoids has been further supported by the fact that the Smoothened-Hedgehog agonist (SAG) has been shown to play a potential neuroprotective effect mediating the activation of the 11ß-hydroxysteroid dehydrogenase type 2 pathway (11ßHSD2). 11ßHSD2, is a NAD-dependent high-affinity enzyme highly expressed in the placenta and the developing CNS (particularly in the GCPs) mainly involved in the local metabolic inactivation of endogenous glucocorticoids, such as prednisolone and corticosterone ( Heine et al, 2011 ; Nguyen et al, 2018 ).…”