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

Gene expression for glial cell fine-derived neurotrophic factor (GDNF) fami ly 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 de ntate granule cell layer. In addition, the number of GDNF mRNA-expressing c ells increased in the cortex and striatum after 2 h or 30 min of MCAO, resp ectively. No changes of neurturin or persephin mRNA expression were detecte d. Both c-Ret and GFR alpha1. mRNA levels were markedly increased in the ip silateral cortex outside the ischemic lesion at 6-24 h after the 2-h insult , whereas GFR alpha2 expression was decreased in cortical areas both within and outside the lesion. Similar increases of c-Ret and GFR alpha1 mRNA lev els were detected in the striatum, and to a lesser extent, in the cortex fo llowing 30 min of MCAO. The 2-h insult also gave rise to transient increase s of c-Ret and GFR alpha1 mRNA in hippocampal. subregions. Thirty minutes a nd 2 h of MCAO lead to elevated c-Ret, and GFR alpha1 or GFR alpha2 naRNA e xpression, respectively, in the ipsilateral ventroposterolateral thalamic n ucleus. Both insults induced increased levels of GFR alpha1 mRNA in the sub ventricular 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 phas e. These changes could enhance neuroprotective and neuroregenerative respon ses both to endogenous and exogenous GDNF ligands. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.