PI3Kγ deficiency enhances seizures severity and associated outcomes in a mouse model of convulsions induced by intrahippocampal injection of pilocarpine

Phosphatidylinositol 3-kinase (PI3K) is an enzyme involved in different pathophysiological processes, including neurological disorders. However, its role in seizures and postictal outcomes is still not fully understood. We investigated the role of PI3K gamma on seizures, production of neurotrophic and inflammatory mediators, expression of a marker for microglia, neuronal death and hippocampal neurogenesis in mice (WT and PI3K gamma(-/-)) subjected to intrahippocampal microinjection of pilocarpine. PI3K gamma(-/-) mice presented a more severe status epilepticus (SE) than WT mice. In hippocampal synaptosomes, genetic or pharmacological blockade of PI3K gamma enhanced the release of glutamate and the cytosolic calcium concentration induced by KCI. There was an enhanced neuronal death and a decrease in the doublecortin positive cells in the dentate gyrus of PI3K gamma(-/-) animals after the induction of SE. Levels of BDNF were significantly increased in the hippocampus of WT and PI3K gamma(-/-) mice, although in the prefrontal cortex, only PI3K gamma(-/-) animals showed significant increase in the levels of this neurotrophic factor. Pilocarpine increased hippocampal microglial immunolabeling in both groups, albeit in the prelimbic, medial and motor regions of the prefrontal cortex this increase was observed only in PI3K gamma(-/-) mice. Regarding the levels of inflammatory mediators, pilocarpine injection increased interleukin (IL) 6 in the hippocampus of WT and PI3K gamma(-/-) animals and in the prefrontal cortex of PI3K gamma(-/-) animals 24 h after the stimulus. Levels of TNF alpha were enhanced in the hippocampus and prefrontal cortex of only PI3K gamma(-/-) mice at this time point. On the other hand, PI3K gamma(-/-) deletion impaired the increase in IL-10 in the hippocampus induced by pilocarpine. In conclusion, the lack of PI3K gamma revealed a deleterious effect in an animal model of convulsions induced by pilocarpine, suggesting that this enzyme may play a protective role in seizures and pathological outcomes associated with this condition. (C) 2015 Elsevier Inc. All rights reserved.