Chemogenetic approaches reveal dual functions of microglia in epilepsy
Dheer, A.; Bosco, D. B.; Zheng, J.; Wang, L.; Zhao, S.; Haruwaka, K.; Yi, M.-H.; Barath, A.; Tian, D.; Wu, L.-J.
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Microglia are key players in maintaining brain homeostasis and exhibit phenotypic alterations in response to epileptic stimuli. However, it is still relatively unknown if these alterations are pro- or anti-epileptic. To unravel this dilemma, we employed chemogenetic manipulation of microglia via of the artificial Gi-Dreadd receptor within a kainic acid (KA) induced murine seizure model. Our results indicate that Gi-Dreadd activation can reduce seizure severity. Additionally, we observed increased interaction between microglia and neuronal soma, which correlated with reduced neuronal hyperactivity. Interestingly, prolonged activation of microglial Gi-Dreadds by repeated doses over 3 days, arrested microglia in a less active, homeostatic-like state, which associated with increased neuronal loss after KA induced seizures. RNAseq analysis revealed that prolonged activation of Gi-Dreadd interferes with interferon {beta} signaling and microglia proliferation. Thus, our findings highlight the importance of microglial activation not only during status epilepticus (SE) but also within later seizure induced pathology.
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