Stroke induces widespread changes of gene expression for glial cell line-derived neurotrophic factor family receptors in the adult rat brain

Abstract

Gene expression for glial cell line-derived neurotrophic factor (GDNF) family ligands and receptors was analyzed with in situ hybridization after two focal ischemic insults of different severities. Focal ischemia was induced in rats by either 30 min or 2 h of middle cerebral artery occlusion (MCAO), causing damage to the striatum only, or involving also the parietal cortex, respectively. We found modest, transient elevation of GDNF mRNA in the dentate granule cell layer. In addition, the number of GDNF mRNA-expressing cells increased in the cortex and striatum after 2 h or 30 min of MCAO, respectively. No changes of neurturin or persephin mRNA expression were detected. Both c-Ret and GFRα1 mRNA levels were markedly increased in the ipsilateral cortex outside the ischemic lesion at 6–24 h after the 2-h insult, whereas GFRα2 expression was decreased in cortical areas both within and outside the lesion. Similar increases of c-Ret and GFRα1 mRNA levels were detected in the striatum, and to a lesser extent, in the cortex following 30 min of MCAO. The 2-h insult also gave rise to transient increases of c-Ret and GFRα1 mRNA in hippocampal subregions. Thirty minutes and 2 h of MCAO lead to elevated c-Ret, and GFRα1 or GFRα2 mRNA expression, respectively, in the ipsilateral ventroposterolateral thalamic nucleus. Both insults induced increased levels of GFRα1 mRNA in the subventricular zone of the lateral ventricle. Our data indicate major changes of GDNF family signaling in the forebrain, regulated mainly through altered receptor levels, in the post-ischemic phase. These changes could enhance neuroprotective and neuroregenerative responses both to endogenous and exogenous GDNF ligands.