# Interaction of Epilepsy and Sleep Disorders in a Mouse Model of Tuberous Sclerosis Complex

> **NIH NIH R56** · WASHINGTON UNIVERSITY · 2020 · $393,750

## Abstract

PROJECT SUMMARY/ABSTRACT
 Tuberous sclerosis complex (TSC) is a relatively common genetic disorder, which features hamartoma
or tumor growth in multiple organs, including the brain, and causes a variety of neurological and neuropsychiatric
symptoms, including epilepsy, intellectual disability, and autism. Mutation of the TSC1 or TSC2 genes leads to
hyperactivation of the mechanistic target of rapamycin (mTOR) pathway, which drives tumor growth and
epileptogenesis in TSC. Epilepsy occurs in up to 90% of TSC patients and is intractable to treatment in the
majority of cases, often leading to life-long disabling seizures. Sleep disorders are also a common occurrence
in TSC and a significant source of decreased quality of life for the patient and family members/caregivers.
Independent of TSC, there is a strong association between epilepsy and sleep, with seizures often arising more
frequently out of sleep, but the mechanistic basis for this relationship is poorly understood and a link between
sleep and seizures in TSC has not been thoroughly investigated. We have recently identified an abnormal sleep
phenotype in a mouse model of TSC (Tsc1GFAPCKO mice) that may at least in part relate to an mTOR-dependent
increase in hypothalamic orexin expression. In this grant proposal, we propose to investigate the
phenomenological and mechanistic relationship between epilepsy and sleep in Tsc1GFAPCKO mice, which also
have progressive seizures, as well as in another mouse model of TSC and an acquired epilepsy model. We
hypothesize that seizures occur more commonly in sleep in Tsc1GFAPCKO mice. Furthermore, we hypothesize
that epilepsy in these mice are at least partly caused by an mTOR-dependent increase in hypothalamic orexin
protein translation and will be responsive to treatment with an orexin antagonist. This work is innovative in
investigating the relationship between sleep and seizures in TSC and identifying a potential role of hypothalamic
orexin in epilepsy. The findings from these studies may have strong impact and translational applications for
developing novel therapies for epilepsy in TSC, in particular orexin antagonists. As TSC is often viewed as a
model genetic disorder for epilepsy and mTORopathies in general, this project may ultimately have relevance to
epilepsy related to other causes.

## Key facts

- **NIH application ID:** 10260074
- **Project number:** 1R56NS115978-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** MICHAEL WONG
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $393,750
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10260074

## Citation

> US National Institutes of Health, RePORTER application 10260074, Interaction of Epilepsy and Sleep Disorders in a Mouse Model of Tuberous Sclerosis Complex (1R56NS115978-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10260074. Licensed CC0.

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