Microglia, the resident microphages of the CNS, are rapidly activated after ischemic stroke. Inhibition of microglial activation may protect the brain by attenuating blood brain barrier damage and neuronal apoptosis after ischemic stroke. However, the mechanisms by which microglia is activated following cerebral ischemia is not well defined. In this study, we investigated the expression of PI3K gamma in normal and ischemic brains and found that PI3K gamma, mRNA and protein are constitutively expressed in normal brain microvessels, but significantly upregulated in postischemic brain primarily in activated microglia following cerebral ischemia. In vitro, the expression of PI3K gamma mRNA and protein was verified in mouse brain endothelial and microglial cell lines. Importantly, absence of PI3K gamma blocked the early microglia activation (at 4 h) and subsequent expansion (at 24-72 h) in PI3K gamma knockout mice. The results suggest that PI3K gamma is an ischemia-responsive gene in brain microglia and contributes to ischemia-induced microglial activation and expansion. (c) 2010 Elsevier Inc. All rights reserved.