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

ISSN： 1460-2156

Source： Brain, Vol.131, Iss.11, 2008-11, pp. : 3019-3033

Disclaimer: Any content in publications that violate the sovereignty, the constitution or regulations of the PRC is not accepted or approved by CNPIEC.

Previous Menu Next

Abstract

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 Ikk conditional knockout mice (LysM-Cre/Ikk^F/F) in which the Ikk gene is specifically deleted in cells of myeloid lineage, including microglia, in the CNS. This deletion reduced IB kinase (IKK) activity in cultured primary microglia by up to 40% compared with wild-type (Ikk^F/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/Ikk^F/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)-α and interleukin (IL)-1. Similarly, neurons in organotypic hippocampal slice cultures (OHSCs) from LysM-Cre/Ikk^F/F mouse brain were less susceptible to KA-induced excitotoxicity compared with wild-type OHSCs, due in part to decreased TNF-α and IL-1 expression. Based on these data, we concluded that IKK/nuclear factor-B dependent microglia activation contributes to KA-induced hippocampal neuronal cell death in vivo through induction of inflammatory mediators.