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Published on: June 12, 2018
Microglial depletion aggravates the severity of acute and chronic seizures in mice
Wenning Wu1, Yujiao Li2, Yujia Wei3
1Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China; Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
Abstract:
Microglia are the resident immune cells of the center nervous system and participate in various neurological diseases. Here we determined the function of microglia in epileptogenesis using microglial ablation approaches. Three different microglia-specific genetic tools were used, CX3CR1CreER/+:R26iDTA/+, CX3CR1CreER/+:R26iDTR/+, and CX3CR1CreER/+:Csf1rFlox/Flox mice. We found that microglial depletion led to worse kainic acid (KA)-induced status epilepticus, higher mortality rate, and increased neuronal degeneration in the hippocampus. In KA-induced chronic spontaneous recurrent seizures, microglial depletion increased seizure frequency, interictal spiking, and seizure duration. Therefore, microglial depletion aggravates the severity of KA-induced acute and chronic seizures. Interestingly, microglial repopulation reversed the effects of depletion upon KA-induced status epilepticus. Our results demonstrate a beneficial role of microglia in suppressing both acute and chronic seizures, suggesting that microglia are a potential therapeutic target for the management of epilepsy.
Insights
Microglia, the brain's immune cells, surprisingly protect against seizures. Depleting microglia worsens epilepsy severity, but their return can restore protection, highlighting their therapeutic potential.
Area of Science:
- Neuroscience
- Immunology
- Neurology
Background:
- Microglia are key immune cells in the central nervous system.
- They are implicated in various neurological diseases, including epilepsy.
- Their precise role in epileptogenesis remains to be fully elucidated.
Purpose of the Study:
- To investigate the function of microglia in the development of epilepsy (epileptogenesis).
- To determine if microglia play a protective or detrimental role in seizure activity.
Main Methods:
- Utilized three distinct microglia-specific genetic ablation tools in mice: CX3CR1CreER/+:R26iDTA/+, CX3CR1CreER/+:R26iDTR/+, and CX3CR1CreER/+:Csf1rFlox/Flox.
- Induced epilepsy using kainic acid (KA) to model both acute status epilepticus and chronic spontaneous recurrent seizures.
- Assessed seizure severity, mortality rates, neuronal degeneration, seizure frequency, interictal spiking, and seizure duration.
Main Results:
- Microglial depletion exacerbated KA-induced status epilepticus, leading to increased mortality and hippocampal neuronal damage.
- In chronic epilepsy models, microglial depletion significantly increased seizure frequency, interictal spiking, and seizure duration.
- Repopulation of microglia reversed the detrimental effects observed after depletion during KA-induced status epilepticus.
Conclusions:
- Microglial depletion worsens the severity of both acute and chronic seizures induced by kainic acid.
- These findings demonstrate a crucial beneficial role for microglia in suppressing seizure activity.
- Microglia represent a promising therapeutic target for epilepsy management.
