Glial Cell Line-Derived Neurotrophic Factor Modulates Kindling and Activation-Induced Sprouting in Hippocampus of Adult Rats

Kindling, a phenomenon in which repeated electrical stimulation of certain forebrain structures leads to an increase in the evoked epileptogenic response, is widely used to investigate the mechanisms of epilepsy. Kindling also results in sprouting of the dentate gyrus mossy fiber pathway and triggers astrocyte hypertrophy and increased volume of the hilus of the dentate gyrus. Our previous studies showed that infusion of the neurotrophin nerve growth factor accelerated the behavioral progression of amygdala kindling and affected kindling-induced structural changes in the brain, whereas intrahilar infusion of another neurotrophin, brain-derived neurotrophic factor, delayed amygdala kindling-induced seizure development and reduced the growth in afterdischarge duration, but had little effect on kindling-induced structural changes. In this paper, we report the effects of infusion of glial cell line-derived neurotrophic factor, a neurotrophic factor of the TGF-beta superfamily having similar central nervous system neuronal targets as brain-derived neurotrophic factor. We show that continuous intraventricular infusion of glial cell line-derived neurotrophic factor inhibits the behavioral progression of perforant path kindling-induced seizures without affecting afterdischarge duration. In addition, we demonstrate that intraventricular administration of glial cell line-derived neurotrophic factor prevents kindling-induced increases in hilar area and blocks mossy fiber sprouting in the CA3 region of the hippocampus. Glial cell line-derived neurotrophic factor did not have a statistically significant effect on the mossy fiber density in the inner molecular layer. Our results raise the possibility that glial cell line-derived neurotrophic factor plays a role in kindling and activation-induced neural growth via mechanisms distinct from those of the neurotrophins.