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Lentiviral Vector-Induced Overexpression of RGMa in the Hippocampus Suppresses Seizures and Mossy Fiber Sprouting

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Abstract

Repulsive guidance molecule a (RGMa) is a membrane-bound protein that inhibits axon outgrowth in the central nervous system. Temporal lobe epilepsy (TLE) is a common neurological disorder characterized by recurrent spontaneous seizures. To explore the role of RGMa in epilepsy, we investigated the expression of RGMa in patients with TLE, pilocarpine-induced rat model, and pentylenetetrazol kindling model of epilepsy, and then we performed behavioral, histological, and electrophysiological analysis by lentivirus-mediated overexpression of RGMa in the hippocampus of animal model. We found that RGMa was significantly decreased in TLE patients and in experimental rats from 6 h to 60 days after pilocarpine-induced seizures. In two types of epileptic animal models, pilocarpine-induced model and pentylenetetrazol kindling model, overexpression of RGMa in the hippocampus of rats exerted seizure-suppressant effects. The reduced spontaneous seizures were accompanied by attenuation of hippocampal mossy fiber sprouting. In addition, overexpression of RGMa inhibited hyperexcitability of hippocampal neurons via suppressing NMDAR-mediated currents in Mg2+-free-induced organotypic slice model. Collectively, these results demonstrate that overexpression of RGMa could be an alternative strategy for epilepsy therapy.

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Acknowledgments

This work was supported by National Natural Science Foundation of China (No. 81071039). The authors sincerely thank the patients and their families for their participation in this study. We thank the Xinqiao Hospital of the Third Military Medical University, Beijing Tiantan Hospital and Xuanwu Hospital of the Capital University of Medical Sciences for their support in brain tissue procurement, and the National Institutes of Health of China and the Ethics Committee on Human Research of the Chongqing Medical University.

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    Authors and Affiliations

    1. Department of Neurology, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, 1 You Yi Road, Chongqing, 400016, China

      Ling Chen, Baobing Gao, Min Fang, Xiujuan Mi, Xin Xu, Wei Wang, Juan Gu, Bo Tang, Yanke Zhang, Zhihua Wang, Ao Zhan, Guojun Chen & Xuefeng Wang

    2. Department of Neurology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China

      Ling Chen

    3. Department of Neurology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, 453100, Henan Province, China

      Jie Li

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    Correspondence to Xuefeng Wang.

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    Informed consents were obtained from all the patients or their guardian. This study was approved by the ethics committees of Chongqing Medical University. All procedures were performed in compliance with the Declaration of Helsinki.

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    The authors declare that they have no competing interests.

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    Ling Chen and Baobing Gao contributed equally to this work.

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    Chen, L., Gao, B., Fang, M. et al. Lentiviral Vector-Induced Overexpression of RGMa in the Hippocampus Suppresses Seizures and Mossy Fiber Sprouting. Mol Neurobiol 54, 1379–1391 (2017). https://doi.org/10.1007/s12035-016-9744-2

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