Publication Abstract Display
Type: Published Manuscript
Title: Profound increase in sensitivity to glutamatergic- but not cholinergic agonist-induced seizures in transgenic mice with astrocyte production of IL-6.
Authors: Samland H, Huitron-Resendiz S, Masliah E, Criado J, Henriksen SJ, Campbell IL
Contact: Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, USA.
Year: 2003
Publication: Journal of Neuroscience Research
Volume: 73 Issue: 2 Pages: 176-87
Abstract: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.
Funding: NIDA:DA DA12065, NIDA:DA DA12444, NIMH:MH MH45294, NIMH:MH MH50426, NIMH:MH MH59745, NIMH:MH MH62261, NIMH:MH MH62962
Keywords: Animals, Astrocytes, Brain, Cholinergic Agonists, Comparative Study, Excitatory Amino Acid Agents, Glial Fibrillary Acidic Protein, Interleukin-6, Kainic Acid, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, N-Methylaspartate, Research Support, U.S. Gov''t, P.H.S., Seizures, Tumor Necrosis Factor-alpha

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