title: Profound increase in sensitivity to glutamatergic- but not cholinergic agonist-induced seizures in transgenic mice with astrocyte production of IL-6.
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.
authors.affiliation: Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Samland
authors.forename: Salvador
authors.initials: S
authors.lastname: Huitron-Resendiz
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Jose
authors.initials: J
authors.lastname: Criado
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Henriksen
authors.forename: Iain L
authors.initials: IL
authors.lastname: Campbell
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018679:Cholinergic Agonists / Q000494:pharmacology*; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology*; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D018679:Cholinergic Agonists; D018683:Excitatory Amino Acid Agents; D005904:Glial Fibrillary Acidic Protein; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016202:N-Methylaspartate; D007608:Kainic Acid