AbstractThe exact role of TNF‐α in excitotoxic neurodegeneration of the brain is unclear. To address this issue, the kainic acid (KA)–induced hippocampal injury model, a well‐characterized model of human neurodegenerative diseases, was used in TNF‐α receptor 1 (TNFR1)–knockout (TNFR1−/−) mice in the present study. After nasal application of a single dose of 40 mg of KA per kilogram body weight, TNFR1−/− mice showed significantly more severe seizures than the wild‐type mice. In addition, obvious neurodegeneration, enhanced microglia activation, and astrogliosis in the hippocampus, as well as increased locomotor activity, were found in TNFR1−/− mice compared with the wild‐type controls 8 days after KA delivery. Moreover, CC chemokine receptor 3 expression on activated microglia was increased 3 days after KA treatment in TNFR1−/− mice, as measured by flow cytometry. These data suggest that TNF‐α may play a protective role through TNFR1 signaling. © 2008 Wiley‐Liss, Inc.