Differential expression of the cell line-derived neurotrophic factor (GDNF) receptor GFRalpha1 in heterozygous Gfralpha1 null-mutant mice after stroke.

Exogenous administration of glial cell line-derived neurotrophic factor (GDNF) reduces ischemia-induced cerebral infarction. Cerebral ischemia induces gene expression of GDNF, GDNF-receptor alpha-1 (GFRalpha-1) and c-Ret, suggesting that a GDNF signaling cascade mechanism may be involved in endogenous neuroprotection during ischemia. In the present study, we examined if this endogenous neuroprotective pathway was altered in Gfralpha-1 deficient mice. Since mice homozygous for the Gfralpha-1 deletion (-/-) die within 24 h of birth, stroke-induced changes in the levels of Gfralpha-1 mRNA were studied in Gfralpha-1 heterozygous (+/-) mice and their wild-type (+/+) littermates. The right middle cerebral artery was transiently ligated for 45 min in anesthetized mice. Animals were killed at 0, 6, 12 and 24 h after the onset of reperfusion and levels of Gfralpha-1 mRNA were measured by in situ hybridization histochemistry. Previously, we showed that Gfralpha-1 (+/-) mice are more vulnerable to focal cerebral ischemia. In the present study, we found that basal levels of GFRalpha-1 mRNA were at similar low levels in cortex and striatum in adult Gfralpha-1 (+/+) and Gfralpha-1 (+/-) mice and that ischemia/reperfusion induced up-regulation of Gfralpha-1 mRNA in the lesioned and contralateral sides of cortex and striatum in both Gfralpha-1 (+/+) and GFRalpha-1 (+/-) mice. However, the ischemia/reperfusion induction of Gfralpha-1 mRNA was significantly higher in the cortex of wild type mice, as compared to Gfralpha-1 (+/-) mice. Moreover, the increased expression of Gfralpha-1 in striatum after reperfusion occurred earlier in the GFRalpha-1 (+/+) than in the Gfralpha-1 (+/-) mice. These results indicate that after ischemia, there is a differential up-regulation of Gfralpha-1 expression in Gfralpha-1 (+/+) and Gfralpha-1 (+/-) mice. Since GDNF has neuroprotective effects, the reduced up-regulation of Gfralpha-1 in Gfralpha-1 (+/-) mice at early time points after ischemia suggests that the responsiveness to GDNF and GDNF receptor mediated neuroprotection is attenuated in these genetically modified animals and may underlie their greater vulnerability.