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Brain Advance Access published online on September 26, 2008
Brain, doi:10.1093/brain/awn230
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© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Role of microglial IKKβ in kainic acid-induced hippocampal neuronal cell death

Ik-Hyun Cho1,*, Jinpyo Hong1,*, Eun Cheng Suh2, Jae Hwan Kim3, Hyunkyoung Lee1, Jong Eun Lee3, Soojin Lee4, Chong-Hyun Kim5, Dong Woon Kim6, Eun-Kyeong Jo7,8, Kyung Eun Lee2, Michael Karin9 and Sung Joong Lee1

1Program in Neuroscience, DRI, and Department of Oral Physiology, School of Dentistry, Seoul National University, 2Department of Pharmacology, School of Medicine, Ewha Womans University, 3Department of Anatomy and Brain Korea 21 Project for Medical Science, College of Medicine, Yonsei University, Seoul, 4Department of Microbiology, School of Bioscience and Biotechnology, Chungnam National University, Daejeon, 5Center for Neural Science, University of Science and Technology, Korea Institute of Science and Technology, Seoul, 6Department of Anatomy, 7Department of Microbiology, 8Infection Signaling Network Research Center, Chungnam National University College of Medicine, Daejeon, Korea and 9Department of Pharmacology, School of Medicine, University of California at San Diego, San Diego, CA, USA

Correspondence to: Sung Joong Lee, PhD, Program in Molecular and Cellular Neuroscience, DRI, and Department of Oral Physiology, School of Dentistry, Seoul National University, Seoul, Korea and Michael Karin, PhD, Department of Pharmacology, School of Medicine, University of California at San Diego, San Diego, CA, USA. E-mail: sjlee87{at}snu.ac.kr

Microglial cells are activated during excitotoxin-induced neurodegeneration. However, the in vivo role of microglia activation in neurodegeneration has not yet been fully elucidated. To this end, we used Ikkβ conditional knockout mice (LysM-Cre/IkkβF/F) in which the Ikkβ gene is specifically deleted in cells of myeloid lineage, including microglia, in the CNS. This deletion reduced I{kappa}B kinase (IKK) activity in cultured primary microglia by up to 40% compared with wild-type (IkkβF/F), and lipopolysaccharide-induced proinflammatory gene expression was also compromised. Kainic acid (KA)-induced hippocampal neuronal cell death was reduced by 30% in LysM-Cre/IkkβF/F mice compared with wild-type mice. Reduced neuronal cell death was accompanied by decreased KA-induced glial cell activation and subsequent expression of proinflammatory genes such as tumour necrosis factor (TNF)-{alpha} and interleukin (IL)-1β. Similarly, neurons in organotypic hippocampal slice cultures (OHSCs) from LysM-Cre/IkkβF/F mouse brain were less susceptible to KA-induced excitotoxicity compared with wild-type OHSCs, due in part to decreased TNF-{alpha} and IL-1β expression. Based on these data, we concluded that IKK/nuclear factor-{kappa}B dependent microglia activation contributes to KA-induced hippocampal neuronal cell death in vivo through induction of inflammatory mediators.

Key Words: excitotoxicity; hippocampus; IKKβ; kainic acid; microglia

Abbreviations: CA1, cornu ammonis 1; CA3, cornu ammonis 3; CD11b, cluster of differentiation molecule 11b; GFAP, glial fibrillary acidic protein; HMGB-1, high-mobility group box-1; Iba-1, ionized calcium binding adaptor molecule-1; IL-1β, interleukin-1β; IKK, I{kappa}B kinase; IR, immunoreactive; KA, kainic acid; LPS, lipopolysaccharide; MCAO, middle cerebral artery occlusion; NF-{kappa}B, nuclear factor-kappa B; NG2, neuron-glial antigen 2; OHSCs, organotypic hippocampal slice cultures; PI, propidium iodide; PM{Phi}, peritoneal macrophages; TLR, toll-like receptor; TNF-{alpha}, tumour necrosis factor-{alpha}; tPA, tissue plasminogen activator

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Received March 11, 2008. Revised July 18, 2008. Accepted August 27, 2008.

*These authors contributed equally to this work.


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