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.