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Published on: June 12, 2018
Microglia and its P2RY12 receptors regulate seizure severity
Leigh Ellen Fremuth1,2,3, Synphane Gibbs-Shelton1,4, Madison Doceti5
1Brain Immunology and Glia Center, University of Virginia, Charlottesville, VA, USA.
Abstract:
Microglia are possible regulators of seizures but previous employed approaches are insufficiently selective of microglial-specific manipulations. To more definitely determine microglial roles in seizure severity, we used the microglial-deficient Csf1r ΔFIRE/ΔFIRE mouse model where mice lack microglia but retain brain border-associated macrophages. Using two experimental paradigms, we confirm that a microglial deficiency exacerbates seizures and facilitates the likelihood of developing spontaneous recurrent seizures, indicating that microglia constrain seizure activity. To gain insights into microglial molecular regulators of seizure severity, we examined P2RY12 contributions and demonstrate that a loss of P2RY12 increased seizure severity in both global and microglial-specific knockout mice indicating that microglia suppress seizure severity. During seizures, P2RY12-deficient microglia displayed altered process complexity, accompanied by increased neuronal activation and reduced inhibitory tone. These results link impaired microglial responses to heightened seizure susceptibility and network excitability. Together, we establish microglia and P2RY12 signaling as protective regulators of seizure activity.
Insights
Microglia protect against seizures. Loss of microglia or P2RY12 signaling in microglia worsens seizure severity and network excitability, establishing them as key regulators of seizure activity.
Area of Science:
- Neuroscience
- Immunology
- Epilepsy Research
Background:
- Microglia, the brain's immune cells, are implicated in seizure regulation, but selective manipulation has been challenging.
- Previous studies lacked specificity, hindering definitive conclusions about microglial roles in epilepsy.
Purpose of the Study:
- To elucidate the specific role of microglia in seizure severity and the development of spontaneous recurrent seizures.
- To investigate the contribution of P2RY12 signaling within microglia to seizure control.
Main Methods:
- Utilized the microglial-deficient Csf1rΔFIRE/ΔFIRE mouse model for selective microglial absence.
- Employed two experimental paradigms to assess seizure activity in the absence of microglia and P2RY12.
- Analyzed microglial process complexity, neuronal activation, and inhibitory tone during seizures.
Main Results:
- Microglial deficiency exacerbated seizures and increased the likelihood of developing spontaneous recurrent seizures.
- Loss of P2RY12 signaling in microglia significantly increased seizure severity.
- P2RY12-deficient microglia showed altered morphology, increased neuronal activation, and reduced inhibitory tone during seizures.
Conclusions:
- Microglia act as critical suppressors of seizure activity and network hyperexcitability.
- P2RY12 signaling in microglia is essential for their protective role in regulating seizure severity.
- These findings identify microglia and P2RY12 as potential therapeutic targets for epilepsy.
