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Inducing Post-Traumatic Epilepsy in a Mouse Model of Repetitive Diffuse Traumatic Brain Injury
Published on: February 10, 2020
Early microglia-mediated neuroinflammation after status epilepticus causes behavioral dysfunction and neurocognitive
Peravina Thergarajan1, Gadeer Al-Hobaish1, Grace Sutherland1
1Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne, Victoria 3004, Australia.
Background:
Neuroinflammation is implicated in epilepsy pathogenesis, and microglia are key immune cells of the brain that participate in neuroinflammatory responses associated with epilepsy. This study investigated the role of early microglial activation following an epileptogenic brain injury on the incidence and severity of epilepsy and associated neurobehavioral impairments in a model of acquired epilepsy.
Methods:
Status epilepticus (SE) was induced in male C57BL/6 mice via electrical stimulation of the ventral hippocampus, while additional mice were enrolled as sham controls (n = 125 total). Following termination of SE, mice received injections of the colony stimulating factor 1 (CSF1) receptor inhibitor PLX5622 (PLX; 50 mg/kg ip twice daily) to suppress microglial activation caused by SE, or vehicle, for seven days. At the end of treatment, the effect of microglial suppression on the neuroinflammatory response to SE was characterised using gene expression, immunohistochemistry, and flow cytometry. Additional mice were followed for four months and underwent a series of neurobehavioral tests and epilepsy assessment.
Results:
PLX treatment significantly reduced Iba1 + cell counts, reduced GFAP + immunoreactivity, and downregulated the expression of proinflammatory cytokines in the hippocampus compared to vehicle following SE, intimating that the neuroinflammatory response of SE was suppressed by PLX. Flow cytometry revealed that SE significantly reduced microglial expression of CX3CR1 and CD206, but increased expression of CD16/32, shifting microglia towards a pro-inflammatory state. However, PLX treatment did not influence the relative expression of these genes. In the chronic stage, SE mice treated with PLX exhibited improved spatial memory (Y-maze test: p = 0.0016) and reduced depressive-like behavior (tail suspension test: p = 0.04; sucrose preference: p = 0.14) compared to vehicle-treated SE mice. However, PLX treatment did not alter the incidence of epilepsy after SE (58 % in vehicle treated mice vs 50 % PLX treated mice; p = 0.65) or seizure frequency in epileptic animals.
Conclusion:
Suppression of microgliosis with PLX eliminates the neuroinflammatory response after SE, and this is associated with prevention of long-term behavioral impairment. However, this intervention does not influence the development of epilepsy. These results demonstrate that acquired epilepsy and its behavioral comorbidities have different pathogenic mechanisms after SE, with early microglial driven neuroinflammation most relevant to the latter.
Insights
Early microglial suppression following brain injury reduced neuroinflammation and improved behavior in an epilepsy model. However, it did not affect epilepsy incidence or severity, suggesting distinct mechanisms for epilepsy and its behavioral comorbidities.
Area of Science:
- Neuroscience
- Immunology
- Epileptology
Background:
- Neuroinflammation, driven by microglia, plays a role in epilepsy development.
- Investigating early microglial activation post-injury is crucial for understanding epilepsy and associated behavioral impairments.
Purpose of the Study:
- To investigate the impact of early microglial activation suppression on epilepsy incidence and severity.
- To assess the effect of microglial suppression on neurobehavioral impairments following an epileptogenic brain injury.
Main Methods:
- Status epilepticus (SE) was induced in mice, followed by treatment with a colony stimulating factor 1 (CSF1) receptor inhibitor (PLX5622) to suppress microglial activation.
- Neuroinflammation was assessed using gene expression, immunohistochemistry, and flow cytometry.
- Long-term epilepsy assessment and neurobehavioral tests were conducted over four months.
Main Results:
- PLX5622 treatment significantly reduced neuroinflammation markers (Iba1, GFAP, proinflammatory cytokines) post-SE.
- SE shifted microglia towards a pro-inflammatory state, but PLX5622 did not alter this specific gene expression.
- PLX5622 treatment improved spatial memory and reduced depressive-like behavior but did not alter epilepsy incidence or seizure frequency.
Conclusions:
- Suppression of microgliosis effectively reduced neuroinflammation and prevented long-term behavioral deficits after SE.
- Early microglial-driven neuroinflammation is linked to behavioral comorbidities but not the development of epilepsy itself.
- Acquired epilepsy and its behavioral comorbidities may arise from distinct pathogenic mechanisms post-SE.
