Modulation of neuropathology and cognitive deficits by lipopolysaccharide preconditioning in a mouse pilocarpine model of status epilepticus

Recent studies indicate that microglia may play a critical role in epileptogenesis during the early post-status epilepticus (SE) period. In this study, we aimed to elucidate the effects of preconditioning of microglia with lipopolysaccharide (LPS) on neuropathology and cognitive deficits in a mouse pilocarpine model of SE. Mice were treated with an intraperitoneal injection of LPS 24 h before SE induction. The open field test at 13 days after SE showed that LPS preconditioning suppressed SE-induced hyperactivity. The Y-maze test at 14 days after SE showed that LPS preconditioning ameliorated SE-induced working memory impairment. The extent of neuronal damage was decreased by LPS preconditioning in the hippocampus of mice euthanized at 15 days after SE. Gene profile analysis of hippocampal microglia at 15 days after SE showed that the expression level of interleukin-1 beta was increased by SE induction but decreased by LPS preconditioning. By contrast, SE induction increased the expression levels of phagocytosis-related genes, and LPS preconditioning further enhanced their expression. Interestingly, LPS preconditioning increased the numerical density of hippocampal microglia expressing the 5D4 keratan sulfate epitope, a population of cells known to be involved in phagocytosis. The voxel density of glutamatergic synapses was increased by SE induction but decreased by LPS preconditioning, while GABAergic synapses were not affected by these procedures. Our findings indicate that LPS preconditioning may in part alleviate SE-related abnormal synaptogenesis and cognitive deficits, and also suggest that modulation of microglial activation during the early post-SE period may be a novel strategy for epilepsy treatment.