In vivo regulation of glial cell line-derived neurotrophic factor-inducible transcription factor by kainic acid

A putative transcription factor induced in vitro by glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor-beta was recently cloned and characterized [Yajima S. et al. (1997) J. Neurosci. 17, 8657-8666]. The messenger RNA of this protein, termed murine GDNF-inducible transcription factor (mGIF, hereafter referred to as GIF), is localized within cortical and hippocampal regions of brain, suggesting that GIF might be regulated by perturbations of these brain regions. In an effort to learn more about the role of GIF in vivo, we examined GIF messenger RNA in the brains of rats treated with the glutamatergic agonist kainic acid. This treatment is known to induce seizures and alter the messenger RNA expression of several growth factors, including GDNF, in several brain regions. Rats were given intraperitoneal saline (1 ml/kg) or kainic acid (15 mg/kg) and were killed at various time-points for in situ hybridization of brain sections with a GIF messenger RNA riboprobe. In saline-treated rats, GIF messenger RNA was present at low levels in cerebral cortex, hippocampus and hippocampal remnants such as the taenia tecta. Kainic acid treatment induced robust increases in GIF messenger RNA in several brain regions, including cerebral cortex, hippocampus, caudate-putamen, nucleus accumbens, and several nuclei of the amygdala and hypothalamus. Most brain regions showed the greatest increase in GIF messenger RNA 4-6 h after kainic acid administration and a return towards normal levels at 48 h. The CA3 region of hippocampus, however, showed a more rapid increase in GIF messenger RNA that was also evident 48 h after kainic acid administration. These results demonstrate that GIF messenger RNA can be regulated in vivo, and that this novel factor warrants further study as a central mediator of GDNF and perhaps other neurotrophic factors.