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Updated: Dec 10, 2025
Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
Microglial mTOR is Neuronal Protective and Antiepileptogenic in the Pilocarpine Model of Temporal Lobe Epilepsy
Xiao-Feng Zhao1, Yuan Liao2, Mahabub Maraj Alam3
1Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, New York 12208 Zhaox1@amc.edu huangy@amc.edu.
Abstract:
Excessive activation of mammalian target of rapamycin (mTOR) signaling is epileptogenic in genetic epilepsy. However, the exact role of microglial mTOR in acquired epilepsy remains to be clarified. In the present study, we found that mTOR is strongly activated in microglia following excitatory injury elicited by status epilepticus. To determine the role of microglial mTOR signaling in excitatory injury and epileptogenesis, we generated mice with restrictive deletion of mTOR in microglia. Both male and female mice were used in the present study. We found that mTOR-deficient microglia lost their typical proliferative and inflammatory responses to excitatory injury, whereas the proliferation of astrocytes was preserved. In addition, mTOR-deficient microglia did not effectively engulf injured/dying neurons. More importantly, microglial mTOR-deficient mice displayed increased neuronal loss and developed more severe spontaneous seizures. These findings suggest that microglial mTOR plays a protective role in mitigating neuronal loss and attenuating epileptogenesis in the excitatory injury model of epilepsy.SIGNIFICANCE STATEMENT The mammalian target of rapamycin (mTOR) pathway is strongly implicated in epilepsy. However, the effect of mTOR inhibitors in preclinical models of acquired epilepsy is inconsistent. The broad presence of mTOR signaling in various brain cells could prevent mTOR inhibitors from achieving a net therapeutic effect. This conundrum has spurred further investigation of the cell type-specific effects of mTOR signaling in the CNS. We found that activation of microglial mTOR is antiepileptogenic. Thus, microglial mTOR activation represents a novel antiepileptogenic route that appears to parallel the proepileptogenic route of neuronal mTOR activation. This may explain why the net effect of mTOR inhibitors is paradoxical in the acquired models of epilepsy. Our findings could better guide the use of mTOR inhibitors in preventing acquired epilepsy.
Insights
Activation of the mammalian target of rapamycin (mTOR) pathway in microglia protects against acquired epilepsy by reducing neuronal loss and seizure severity. This microglial mTOR activation is antiepileptogenic.
Area of Science:
- Neuroscience
- Cell Biology
- Epilepsy Research
Background:
- Mammalian target of rapamycin (mTOR) signaling is implicated in epilepsy, but its role in acquired forms is unclear.
- Microglial mTOR activation occurs after excitatory brain injury, yet its specific function in epileptogenesis is unknown.
Purpose of the Study:
- To investigate the role of microglial mTOR signaling in acquired epilepsy following excitatory injury.
- To determine if microglial mTOR activation is protective or detrimental in epilepsy models.
Main Methods:
- Generated mice with targeted deletion of mTOR specifically in microglia.
- Exposed mice to an epilepsy model induced by status epilepticus.
- Assessed microglial responses, neuronal loss, astrocyte proliferation, and seizure activity.
Main Results:
- Microglial mTOR deficiency impaired microglial proliferation and inflammatory responses to injury.
- Mice lacking microglial mTOR showed increased neuronal death and exacerbated spontaneous seizures.
- Astrocyte proliferation remained unaffected by microglial mTOR deletion.
Conclusions:
- Microglial mTOR activation plays a protective role in acquired epilepsy, mitigating neuronal injury and reducing seizure severity.
- Targeting microglial mTOR may offer a novel therapeutic strategy for acquired epilepsy, distinct from neuronal mTOR pathways.
