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Deletion of mTOR in Reactive Astrocytes Suppresses Chronic Seizures in a Mouse Model of Temporal Lobe Epilepsy

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Abstract

Germline and somatic mutations in key genes of the mammalian target of rapamycin (mTOR) pathway have been identified in seizure-associated disorders. mTOR mutations lead to aberrant activation of mTOR signaling, and, although affected neurons are critical for epileptogenesis, the role of mTOR activation in glial cells remains poorly understood. We previously reported a consistent activation of the mTOR pathway in astrocytes in the epileptic foci of temporal lobe epilepsy. In this study, it was demonstrated that mTOR deletion from reactive astrocytes prevents increases in seizure frequency over the disease course. By using a tamoxifen-inducible mTOR conditional knockout system and kainic acid, a model was developed that allowed astrocyte-specific mTOR gene deletion in mice with chronic epilepsy. Animals in which mTOR was deleted from 44 % of the astrocyte population exhibited a lower seizure frequency compared with controls. Down-regulation of mTOR significantly ameliorated astrogliosis in the sclerotic hippocampus but did not rescue mossy fiber sprouting. In cultured astrocytes, the mTOR pathway modulated the stability of the astroglial glutamate transporter 1 (Glt1) and influenced the ability of astrocytes to remove extracellular glutamate. Taken together, these data indicate that astrocytes with activated mTOR signaling may provide conditions that are favorable for spontaneous recurrent seizures.

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Acknowledgments

We thank Prof. Weimin Tong, PUMC, for kindly providing genetic tools. We thank Dr. Susan Amara for providing CMV-hEAAT2 plasmid. This work was supported by the research grants from the National Basic Research Program of China (2013CB531301, 2012CB517902), the National Natural Science Foundation of China (31430048, 81471325, 31222031), the Fundamental Research Funds for the Central Universities (2012S05), and the PUMC Youth Fund (2012 J09, NCET-12-0071, 33320140172).

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    1. National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Dong Dan San Tiao, Beijing, 100730, China

      Xueqin Wang, Longze Sha, Nannan Sun, Yan Shen & Qi Xu

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    1. Xueqin Wang
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    Xueqin Wang and Longze Sha contributed equally to this work.

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    Wang, X., Sha, L., Sun, N. et al. Deletion of mTOR in Reactive Astrocytes Suppresses Chronic Seizures in a Mouse Model of Temporal Lobe Epilepsy. Mol Neurobiol 54, 175–187 (2017). https://doi.org/10.1007/s12035-015-9590-7

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