title: Involvement of interleukin-1 in lipopolysaccaride-induced microglial activation and learning and memory deficits.
abstract: We have developed an animal model of learning and memory impairment associated with activation of microglia in the mouse brain. Injection of lipopolysaccharide into the CA1 region of the mouse hippocampus resulted in an increased production of inflammatory cytokines, such as interleukin-1β. Immunostaining for interleukin-1β revealed an increase in the signal at 6 hr after lipopolysaccharide injection. Immunopositive cells for interleukin-1β were colocalized with those immunopositive for CD11b. When subacute lipopolysaccharide treatment (20 μg/2 μl/injection, bilaterally for 5 consecutive days) was performed, long-term activation of microglia and learning and memory deficits as evaluated using a step-through passive avoidance test were observed in the wild-type mice. Gene expression of the N-methyl-D-aspartate receptor NR1 and NR2A subunits was also decreased by the lipopolysaccharide treatment. In contrast, activation of microglia and the associated behavioral deficits were not observed in mice lacking interleukin-1α and -1β following the subacute lipopolysaccharide treatment, together with little change in the gene expression of NR1 and NR2A subunits. However, the subacute lipopolysaccharide treatment produced almost similar changes in those parameters in the tumor necrosis factor-α knockout mice as in the wild-type animals. The injection of interleukin-1β neutralizing antibody with lipopolysaccharide for 5 consecutive days resulted in the improvement of lipopolysaccharide-induced learning and memory deficits. These findings suggest that the expression of interleukin-1 plays an important role in lipopolysaccharide-induced activation of microglia and the associated functional deficits in learning and memory.
authors.affiliation: Department of Biochemical Toxicology, School of Pharmacy, Showa University, Tokyo, Japan. stanaka@pharm.showa-u.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.forename: H
authors.initials: H
authors.lastname: Kondo
authors.forename: K
authors.initials: K
authors.lastname: Kanda
authors.forename: T
authors.initials: T
authors.lastname: Ashino
authors.forename: T
authors.initials: T
authors.lastname: Nakamachi
authors.forename: K
authors.initials: K
authors.lastname: Sekikawa
authors.forename: Y
authors.initials: Y
authors.lastname: Iwakura
authors.forename: S
authors.initials: S
authors.lastname: Shioda
authors.forename: S
authors.initials: S
authors.lastname: Numazawa
authors.forename: T
authors.initials: T
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015870:Gene Expression; D006624:Hippocampus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism*; D007859:Learning Disabilities / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology / Q000633:toxicity*; D008297:Male; D008569:Memory Disorders / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D007375:Interleukin-1; D008070:Lipopolysaccharides; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate