TNF-α receptor 1 deficiency enhances kainic acid-induced hippocampal injury in mice

The 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.