Abstract
Events of status epilepticus (SE) trigger the development of temporal lobe epilepsy (TLE), a type of focal epilepsy that is commonly drug-resistant and is highly comorbid with cognitive deficits. While SE-induced hippocampal injury, accompanied by gliosis and neuronal loss, typically disrupts cognitive functions resulting in memory defects, it is not definitively known how. Our previous studies revealed extensive hippocampal microgliosis that peaked between 2 and 3 weeks after SE and paralleled the development of cognitive impairments, suggesting a role for reactive microglia in this pathophysiology. Microglial survival and proliferation are regulated by the colony-stimulating factor 1 receptor (CSF1R). The CSF1R inhibitor PLX3397 has been shown to reduce/deplete microglial populations and improve cognitive performance in models of neurodegenerative disorders. Therefore, we hypothesized that suppression of microgliosis with PLX3397 during epileptogenesis may attenuate the hippocampal-dependent spatial learning and memory deficits in the rat pilocarpine model of SE and acquired TLE. Different groups of control and SE rats were fed standard chow (SC) or chow with PLX3397 starting immediately after SE and for 3 weeks. Novel object recognition (NOR) and Barnes maze (BM) were performed to determine memory function between 2 and 3 weeks after SE. Then microglial populations were assessed using immunohistochemistry. Control rats fed with either SC or PLX3397 performed similarly in both NOR and BM tests, differentiating novel vs. familiar objects in NOR, and rapidly learning the location of the hidden platform in BM. In contrast, both SE groups (SC and PLX3397) showed significant deficits in both NOR and BM tests compared to controls. Both PLX3397-treated control and SE groups had significantly decreased numbers of microglia in the hippocampus (60%) compared to those in SC. In parallel, we found that PLX3397 treatment also reduced SE-induced hippocampal astrogliosis. Thus, despite drastic reductions in microglial cells, memory was unaffected in the PLX3397-treated groups compared to those in SC, suggesting that remaining microglia may be sufficient to help maintain hippocampal functions. In sum, PLX3397 did not improve or worsen the memory deficits in rats that sustained pilocarpine-induced SE. Further research is required to determine whether microglia play a role in cognitive decline during epileptogenesis.
Highlights
Temporal lobe epilepsy (TLE) is a type of focal epilepsy that is commonly drug-resistant [1] and is highly comorbid with cognitive deficits [2]
The C+standard chow (SC) and C+PLX groups had significantly greater RI than the status epilepticus (SE)+SC or SE+PLX groups [Main effect, two-way ANOVA, F(1,30) = 15.32, p = 0.0005] (Figure 3C), suggesting that the control animals treated with CS or PLX had greater memory of the familiar objects compared to both SE groups. Taken together these findings indicate that SE provokes memory defects and that PLX treatment had no effect on the recognition memory of either control or SE rats
To understand the contribution of microglial cells to the cognitive dysfunction associated with epileptogenesis we used a dietary treatment with the drug PLX3397 to decrease the population of microglial cells during this critical period
Summary
Temporal lobe epilepsy (TLE) is a type of focal epilepsy that is commonly drug-resistant [1] and is highly comorbid with cognitive deficits [2]. In TLE, the hippocampus is often damaged as evidenced by the presence of extensive gliosis and severe neuronal loss, known as hippocampal sclerosis. These disruptions to the hippocampal circuitry interfere with essential functions such as processing and consolidation of short- and long-term memories thereby resulting in learning and memory dysfunctions [2]. Extensive research in animal models of acquired TLE, typically induced with a single episode of status epilepticus (SE), a long-lasting seizure (>1 h), support that SE-induced hippocampal injury in an otherwise healthy system contributes to epileptogenesis, as well as memory decline [4]; though the mechanisms underlying memory loss after SE and TLE are still not fully understood. Our previous studies point to microglial cells, the resident immune cells of the brain, as potential mediators of learning and memory defects during SE-induced epileptogenesis [5,6,7,8,9]
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