GDNF family ligands and receptors are differentially regulated after braininsults in the rat

Expression of mRNAs for glial cell line-derived neurotrophic factor (GDNF), neurturin (NTN) and their receptors was studied in adult rat brain using i n situ hybridization after 40 kindling-evoked, rapidly recurring seizures o r 10 min of global forebrain ischaemia. Following seizures, GDNF and NTN mR NAs were elevated in dentate granule cells, and c-Ret mRNA in hilar neurons and nonpyramidal cells in CA1 and CA3 regions. GFR alpha-1 mRNA levels sho wed more widespread increases in the dentate granule cell layer and hilus, CA1 and CA3 pyramidal layers, basolateral amygdala and parietal cortex. The expression of GFR alpha-2 mRNA increased in the piriform cortex and decrea sed in the CA1 region and basolateral amygdala. Forebrain ischaemia induced elevated expression of GDNF mRNA in dentate granule cells, GFR alpha-1 mRN A in the dentate granule cell layer, hilus and CA3 pyramidal layer, and GFR alpha-2 mRNA in the parietal cortex. The gene expression patterns observed here suggest that GDNF and NTN may act as target-derived factors, but also in an autocrine or paracrine manner. GFR alpha-1 can be coexpressed with G FR alpha-2 and c-Ret mRNAs in the same hippocampal or thalamic neurons, but other neurons contain GFR alpha-1 alone or together with c-Ret mRNA, The g ene expression changes for the ligands, and the receptor components are reg ion-, cell- and insult-specific, and occur independently of each other, mai nly within 24 h after seizures or ischaemia. This dynamic regulation of GDN F and NTN circuits primarily at the receptor level may be important for the effectiveness of neuroprotective responses but could also trigger plastic changes, e.g. those underlying the development of epileptic syndromes.