Profound increase in sensitivity to glutamatergic- but not cholinergic agonist-induced seizures in transgenic mice with astrocyte production of IL-6
Article first published online: 23 MAY 2003
Copyright © 2003 Wiley-Liss, Inc.
Journal of Neuroscience Research
Volume 73, Issue 2, pages 176–187, 15 July 2003
How to Cite
Samland, H., Huitron-Resendiz, S., Masliah, E., Criado, J., Henriksen, S. J. and Campbell, I. L. (2003), Profound increase in sensitivity to glutamatergic- but not cholinergic agonist-induced seizures in transgenic mice with astrocyte production of IL-6. J. Neurosci. Res., 73: 176–187. doi: 10.1002/jnr.10635
- Issue published online: 24 JUN 2003
- Article first published online: 23 MAY 2003
- Manuscript Accepted: 6 MAR 2003
- Manuscript Revised: 23 FEB 2003
- Manuscript Received: 12 SEP 2002
- NIH. Grant Numbers: MH50426, MH62261, DA12444, DA12065, MH59745, MH45294, MH62962
- glial fibrillary acidic protein;
- kainic acid
Transgenic mice with glial fibrillary acidic protein (GFAP) promoter driven-astrocyte production of the cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF) were used to determine whether the pre-existing production of these cytokines in vivo might modulate the sensitivity of neurons to excitotoxic agents. Low doses of kainic acid (5 mg/kg) that produced little or no behavioral or electroencephalogram (EEG) alterations in wild type or glial fibrillary acidic protein (GFAP)-TNF animals induced severe tonic-clonic seizures and death in GFAP-IL6 transgenic mice of 2 or 6 months of age. GFAP-IL6 mice were also significantly more sensitive to N-methyl-D-aspartate (NMDA)- but not pilocarpine-induced seizures. Kainic acid uptake in the brain of the GFAP-IL6 mice was higher in the cerebellum but not in other regions. Kainic acid binding in the brain of GFAP-IL6 mice had a similar distribution and density as wild type controls. In the hippocampus of GFAP-IL6 mice that survived low dose kainic acid, there was no change in the extent of either neurodegeneration or astrocytosis. Immunostaining revealed degenerative changes in gamma aminobutyric acid (GABA)- and parvalbumin-positive neurons in the hippocampus of 2-month-old GFAP-IL6 mice which progressed to the loss of these cells at 6 months of age. Thus, GFAP-IL6 but not GFAP-TNF mice showed markedly enhanced sensitivity to glutamatergic- but not cholinergic-induced seizures and lethality. This may relate, in part, to a compromise of inhibitory interneuron function. Therefore, pre-existing IL-6 production and inflammation in the central nervous system (CNS) not only causes spontaneous neurodegeneration but also synergizes with other neurotoxic insults to induce more severe acute functional neurological impairment. © 2003 Wiley-Liss, Inc.