Abstract
Status epilepticus (SE) is defined by the occurrence of prolonged “non-stop” seizures that last for at least 5 min. SE provokes inflammatory responses including the activation of microglial cells, the brain’s resident immune cells, which are thought to contribute to the neuropathology and pathophysiology of epilepsy. Microglia are professional phagocytes that resemble peripheral macrophages. Upon sensing immune disturbances, including SE, microglia become reactive, produce inflammatory cytokines, and alter their actin cytoskeleton to transform from ramified to amoeboid shapes. It is widely known that SE triggers time-dependent microglial expression of pro-inflammatory cytokines that include TNFα and IL-1β. However, less is known in regards to the spatiotemporal progression of the morphological changes, which may help define the extent of microglia reactivity after SE and potential function (surveillance, inflammatory, phagocytic). Therefore, in this study, we used the microglia/macrophage IBA1 marker to identify and count these cells in hippocampi from control rats and at 4 h, 3 days, and 2 weeks after a single episode of pilocarpine-induced SE. We identified, categorized, and counted the IBA1-positive cells with the different morphologies observed after SE in the hippocampal areas CA1, CA3, and dentate gyrus. These included ramified, hypertrophic, bushy, amoeboid, and rod. We found that the ramified phenotype was the most abundant in control hippocampi. In contrast, SE provoked time-dependent changes in the microglial morphology that was characterized by significant increases in the abundance of bushy-shaped cells at 4 h and amoeboid-shaped cells at 3 days and 2 weeks. Interestingly, a significant increase in the number of rod-shaped cells was only evident in the CA1 region at 2 weeks after SE. Taken together, these data suggest that SE triggers time-dependent alterations in the morphology of microglial cells. This detailed description of the spatiotemporal profile of SE-induced microglial morphological changes may help provide insight into their contribution to epileptogenesis.
Highlights
Status epilepticus (SE) is defined by the occurrence of prolonged “non-stop” seizures that last for at least 5 min [1]
We previously reported that a single episode of SE provoked an increase in the immunoreactivity for the microglial/macrophage marker ionized calcium-binding adaptor molecule 1 (IBA1) in the hippocampus that peaked at 2 weeks after the induction of SE [22]
The main findings of this study are that a single episode of SE triggers: [1] an increase in the number of microglia/macrophages in the hippocampus that is significantly different from controls at 2 weeks after SE (Figure 1); [2] time-dependent changes that are characterized by an increase in the population of microglia/ macrophage with bushy shapes which peak at 4 h and are followed by an increase in the abundance of amoeboid cells at 3 days and 2 weeks after the prolonged seizures (Figures 3 and 4); and [3] a significant increase in the number of rod-shaped cells was only evident in the CA1 region at 2 weeks post-SE (Figures 3 and 4)
Summary
Status epilepticus (SE) is defined by the occurrence of prolonged “non-stop” seizures that last for at least 5 min [1]. Reactive microglia go through morphological changes that range from a phenotype of small cell bodies with vastly ramified processes (surveilling microglia) to small amoeboid shapes with little to no processes (activated/phagocytic) that can alternate between transitional states/phenotypes that include slightly enlarged cell bodies with thickened processes that may be long or short [10,11,12,13,14,15,16] Both inflammatory and morphological microglial alterations have been widely described in human epileptic brain tissues [4, 17,18,19,20,21] as well as in animal models of SE and experimental epilepsy [4, 22,23,24,25,26,27,28]. Understanding these phenotypes may help define the extent of microglia reactivity and potential function after SE
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