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Chemogenetic approaches reveal dual functions of microglia in seizures
Aastha Dheer1, Dale B Bosco1, Jiaying Zheng2
1Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Abstract:
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 using the artificial Gi-Dreadd receptor within a kainic acid (KA) induced murine seizure model. Our results indicate that acute Gi-Dreadd activation with Clozapine-N-Oxide 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 of CNO 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 β signaling and microglia proliferation. Thus, our findings highlight the importance of microglial Gi signaling not only during status epilepticus (SE) but also within later seizure induced pathology.
Insights
Microglia modulation impacts epilepsy. Acute activation reduced seizure severity, while prolonged activation worsened neuronal loss by altering microglia
Area of Science:
- Neuroscience
- Immunology
- Epilepsy Research
Background:
- Microglia are crucial for brain homeostasis.
- Their role in epilepsy (pro- or anti-epileptic) remains unclear.
- Epileptic stimuli induce microglial phenotypic changes.
Purpose of the Study:
- To investigate the dual role of microglial Gi signaling in epilepsy.
- To determine if microglial modulation can alter seizure severity and pathology.
Main Methods:
- Used a kainic acid (KA) induced murine seizure model.
- Employed chemogenetics to manipulate microglia via Gi-Dreadd receptors.
- Administered Clozapine-N-Oxide (CNO) for acute and prolonged activation.
- Performed RNAseq analysis.
Main Results:
- Acute Gi-Dreadd activation reduced seizure severity and neuronal hyperactivity.
- Increased microglia-neuron soma interaction was observed with acute activation.
- Prolonged activation led to a less active microglial state.
- Prolonged activation exacerbated neuronal loss post-seizure.
- RNAseq revealed interference with interferon β signaling and microglia proliferation.
Conclusions:
- Microglial Gi signaling plays a critical role in both acute and chronic epilepsy.
- Acute microglial activation may be neuroprotective in seizures.
- Prolonged microglial suppression can be detrimental, increasing seizure-induced pathology.
- Findings highlight the importance of temporal control in microglial-targeted epilepsy therapies.
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