Inhibition of the mammalian target of rapamycin blocks epilepsy progression in NS-Pten conditional knockout mice

Authors

  • C. Nicole Sunnen,

    1. The Cain Foundation Laboratories and The Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, Texas, U.S.A.; Departments of
    2. Neuroscience
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  • Amy L. Brewster,

    1. The Cain Foundation Laboratories and The Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, Texas, U.S.A.; Departments of
    2. Neuroscience
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  • Joaquin N. Lugo,

    1. The Cain Foundation Laboratories and The Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, Texas, U.S.A.; Departments of
    2. Pediatrics
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  • Fabiola Vanegas,

    1. The Cain Foundation Laboratories and The Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, Texas, U.S.A.; Departments of
    2. Pediatrics
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  • Eric Turcios,

    1. The Cain Foundation Laboratories and The Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, Texas, U.S.A.; Departments of
    2. Pediatrics
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  • Shivani Mukhi,

    1. The Cain Foundation Laboratories and The Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, Texas, U.S.A.; Departments of
    2. Pediatrics
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  • Deena Parghi,

    1. Pathology, Baylor College of Medicine, Houston, Texas, U.S.A.
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  • Gabriella D’Arcangelo,

    1. Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, New Jersey, U.S.A.
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  • Anne E. Anderson

    1. The Cain Foundation Laboratories and The Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, Texas, U.S.A.; Departments of
    2. Neuroscience
    3. Pediatrics
    4. Department of Neurology, Baylor College of Medicine, Houston, Texas, U.S.A.
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Address correspondence to Anne E. Anderson, M.D., The Cain Foundation Laboratories and The Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, 1250 Moursund St., Suite 1225, Houston, TX 77030, U.S.A. E-mail: annea@bcm.tmc.edu

Summary

Purpose:  Increased activity of mTOR Complex 1 (mTORC1) has been demonstrated in cortical dysplasia and tuberous sclerosis complex, as well as in animal models of epilepsy. Recent studies in such models revealed that inhibiting mTORC1 with rapamycin effectively suppressed seizure activity. However, seizures can recur after treatment cessation, and continuous rapamycin exposure can adversely affect animal growth and health. Here, we evaluated the efficacy of an intermittent rapamycin treatment protocol on epilepsy progression using neuron subset-specific-Pten (NS-Pten) conditional knockout mice.

Methods:  NS-Pten knockouts were treated with a single course of rapamycin during postnatal weeks 4 and 5, or intermittently over a period of 5 months. Epileptiform activity was monitored using video–electroencephalography (EEG) recordings, and mossy fiber sprouting was evaluated using Timm staining. Survival and body weight were assessed in parallel.

Key Findings:  NS-Pten knockouts treated with a single course of rapamycin had recurrence of epilepsy 4–7 weeks after treatment ended. In contrast, epileptiform activity remained suppressed, and survival increased if knockout mice received additional rapamycin during weeks 10–11 and 16–17. Aberrant mossy fiber sprouting, present by 4 weeks of age and progressing in parallel with epileptiform activity, was also blocked by rapamycin.

Significance:  These findings demonstrate that a single course of rapamycin treatment suppresses epileptiform activity and mossy fiber sprouting for several weeks before epilepsy recurs. However, additional intermittent treatments with rapamycin prevented this recurrence and enhanced survival without compromising growth. Therefore, these studies add to the growing body of evidence implicating an important role for mTORC1 signaling in epilepsy.

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