Microglial mTOR is Neuronal Protective and Antiepileptogenic in the Pilocarpine Model of Temporal Lobe Epilepsy
| Autor: | Xinjun Cindy Zhu, Matthew A. Adamo, Joseph E. Mazurkiewicz, Ramkumar Mathur, Mahabub Maraj Alam, Xiao-Feng Zhao, Yuan Liao, Yunfei Huang, Paul J. Feustel |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Cell Status epilepticus Epileptogenesis 03 medical and health sciences Epilepsy Mice 0302 clinical medicine Phagocytosis Medicine Animals PI3K/AKT/mTOR pathway Research Articles Neurons Microglia business.industry General Neuroscience TOR Serine-Threonine Kinases Pilocarpine medicine.disease Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Epilepsy Temporal Lobe Astrocytes Excitatory postsynaptic potential Female medicine.symptom business Neuroscience 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | J Neurosci |
| Popis: | 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 STATEMENTThe 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. |
| Databáze: | OpenAIRE |
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