Rapid and transient increases in cellular immediate early gene and neuropeptide mRNAs in cortical and limbic areas after amygdaloid kindling seizures in the rat

Abstract

Changes in transcription factor and neuropeptide gene expression are likely to be involved in the cascade of genetic and molecular events leading to permanent changes in neuronal activity associated with kindling and epilepsy. Both acute-transient and delayed-sustained changes in transcription factor or immediate early gene (IEG) activity have previously been reported in response to different stimuli. In the present study in situ hybridization was used to investigate the possible time course (30 min-8 week) of IEG and neuropeptide mRNA induction in forebrain in a kindling model of epilepsy. Kindling was produced by daily unilateral stimulation of the amygdala. IEG mRNAs were detected using [35S]-labelled oligonucleotide probes specific for c-fos, c-jun, NGFI-A (PC1) and PC3 transcripts. Possible changes in the level of mRNAs encoding the neuropeptides somatostatin (SOM) and neuropeptide Y (NPY) were also studied. Stimulation-induced seizures produced dramatic bilateral increases in all IEG mRNAs in the dentate gyrus after 30 min to 1 h. Ipsilateral or bilateral increases in c-fos and PC3 mRNA were observed in the piriform cortex of individual animals at 30 min post-stimulation. While the distribution and apparent basal expression of the different IEGs varied (NGFI-A and c-jun > c-fos and PC3), the degree of induction in the dentate gyrus was similar for all IEGs studied (i.e. 200-300%). No long-term changes in IEG mRNA expression were detected beyond 2 h and up to 8 week after the last seizure. Increased levels of preproSOM and preproNPY mRNAs were consistently observed in hilar interneurons, but not in pyramidal or granule cells of the hippocampus, after 1-2 h. These increases were not maintained at later times. The short-term effects on IEG and neuropeptide mRNAs observed suggest that these changes are consequence of seizure activity with the development of kindling. In contrast, no evidence was found of any substantial, long-lasting effects on these parameters associated with the established kindled state.