title: Kainic acid-activated microglia mediate increased excitability of rat hippocampal neurons in vitro and in vivo: crucial role of interleukin-1beta.
abstract: OBJECTIVE
  It is known that highly activated microglia and the consequent production of inflammatory cytokines were associated with neuroexcitotoxic injuries. The present study was carried out to explore whether interleukin-1beta (IL-1beta), a proinflammatory cytokine produced in abundance by activated microglia, mediates increased excitability of hippocampal neurons and the related molecular mechanisms.
  
  
  METHODS
  Primary cultured microglia were activated by kainic acid (KA), and the KA-treated microglial conditioned medium (KA-MCM) was collected. KA-MCM with or without anti-rat IL-1beta monoclonal neutralizing antibody was then injected into the rat in the right cerebral ventricle, or primary cultured hippocampal neurons were treated with the above-mentioned KA-MCM. The population spike amplitude changes in the CA3 region were assessed by electrophysiological recording in vivo. Western blot and RT-PCR assay were performed to investigate the expression changes of N-methyl-D-aspartate receptor subunit 1 (NMDAR1) and inducible nitric oxide synthase (iNOS) expression in hippocampal neurons.
  
  
  RESULTS
  Primary cultured microglia were significantly activated by KA with increased IL-1beta levels. Interestingly, intracerebroventricular administration of KA-MCM to rats resulted in enhancement of population spike amplitude in the CA3 region and in upregulation of NMDAR1 and iNOS expression in the hippocampus, which was partially attenuated by anti-rat IL-1beta antibody. Furthermore, the changes in NMDAR1 and iNOS expression in the rat hippocampus were verified by incubation of primary cultured hippocampal neurons with KA-MCM.
  
  
  CONCLUSIONS
  This study provides evidence that KA-activated microglia mediate increased excitability of hippocampal neurons in vitro and in vivo and that IL-1beta may be one of the main causes of this event.
authors.affiliation: Department of Brain Research, Division of Anatomy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Honghua
authors.initials: H
authors.lastname: Zheng
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Hu
authors.initials: H
authors.lastname: Zhao
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Zhengli
authors.initials: Z
authors.lastname: Li
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000276:immunology; D000818:Animals; D000831:Animals, Newborn; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004660:Encephalitis / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D004827:Epilepsy / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000276:immunology* / Q000503:physiopathology; D053583:Interleukin-1beta / Q000378:metabolism*; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D009410:Nerve Degeneration / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism* / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D017077:Culture Media, Conditioned; D018690:Excitatory Amino Acid Agonists; D053583:Interleukin-1beta; D007608:Kainic Acid; D009498:Neurotoxins; D052247:Nitric Oxide Synthase Type II; D016194:Receptors, N-Methyl-D-Aspartate