title: Lipopolysaccharide-induced microglial activation induces learning and memory deficits without neuronal cell death in rats.
abstract: We used lipopolysaccharide (LPS) to activate microglia that play an important role in the brain immune system. LPS injected into the rat hippocampus CA1 region activated microglial cells resulting in an increased production of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha in the hippocampus during the initial stage of treatment. Immunostaining for IL-1beta was increased at 6 hr after LPS injection. IL-1beta-immunopositive cells were co-localized with immunostaining for CD11b. Subacute treatment with LPS by the same route for 5 days caused long-term activation of microglia and induced learning and memory deficits in animals when examined with a step-through passive avoidance test, but histochemical analysis showed that neuronal cell death was not observed under these experimental conditions. The increased expression of the heme oxygenase-1 (HO-1) gene, an oxidative stress maker, was observed. However, the genetic expression of brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, decreased during the course of LPS treatment. We found decreases in [3H]MK801 binding in the hippocampus CA1 region by LPS-treatment for 5 days. The data shows that glutamatergic transmission was attenuated in the LPS-treated rats. These results suggest that long-term activation of microglia induced by LPS results in a decrease of glutamatergic transmission that leads to learning and memory deficits without neuronal cell death. The physiologic significance of these findings is discussed.
authors.affiliation: Department of Biochemical Toxicology, School of Pharmaceutical Sciences, Tokyo, Japan. stanaka@pharm.showa-u.ac.jp
authors.forename: Sachiko
authors.initials: S
authors.lastname: Tanaka
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Ide
authors.forename: Toshiomi
authors.initials: T
authors.lastname: Shibutani
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Ohtaki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Numazawa
authors.forename: Seiji
authors.initials: S
authors.lastname: Shioda
authors.forename: Takemi
authors.initials: T
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D001362:Avoidance Learning; D015152:Blotting, Northern; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007375:Interleukin-1 / Q000378:metabolism; D007859:Learning Disabilities / Q000139:chemically induced* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008569:Memory Disorders / Q000139:chemically induced* / Q000473:pathology; D017628:Microglia / Q000187:drug effects*; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D020813:Receptor, trkB / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018691:Excitatory Amino Acid Antagonists; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016291:Dizocilpine Maleate; D051547:Heme Oxygenase-1; D020813:Receptor, trkB