A novel study led by Michael Wong, MD, PhD, suggests that sleep disturbances in tuberous sclerosis complex (TSC) may be driven by overactivation of the mTOR pathway, which increases levels of the wake-promoting molecule orexin in the brain.
TSC is a genetic disorder which produces overactivation of the mechanistic target of rapamycin (mTOR) pathway. This overactivity leads to various neurological symptoms, including epilepsy and sleep disorders. Sleep disturbances are common in individuals with TSC, leading to insomnia, increased awakenings, and decreased REM sleep, often significantly impacting their quality of life. Despite their prevalence, the underlying causes of these sleep problems in TSC are not well understood. This study aimed to investigate the mechanisms of sleep dysfunction in a mouse model of TSC, specifically focusing on the mTOR pathway and its interaction with orexin, a naturally occurring molecule in the brain involved in regulating sleep and wakefulness.
The study utilized a mouse model (Tsc1GFAPCKO mice) that mimics TSC by inactivating the Tsc1 gene in neurons and astrocytes, leading to mTOR pathway hyperactivation. These mice exhibited significant sleep abnormalities, including decreased REM (Rapid Eye Movement) sleep and impaired differentiation between light and dark phase sleep-wake cycles. Specifically, they showed increased awake time during the light cycle (when mice typically sleep more) and a general lack of difference in sleep-wake patterns between light and dark phases, unlike control mice.
In the Tsc1GFAPCKO mice, both mTOR activity and the expression of orexin were found to be increased in the hypothalamus, a brain region critical for regulating sleep. Orexin-expressing neurons in these mice also showed increased cell size, a common feature of mTOR hyperactivation. These findings suggest a possible direct link between mTOR overactivity and increased orexin levels in the hypothalamus, contributing to the observed sleep dysfunction.
Experiments with cultured hypothalamic neurons from Tsc1GFAPCKO mice further supported that the increased mTORC1 activation and orexin expression occur directly within the orexin neurons themselves.
Treatment with rapamycin, an mTOR inhibitor, successfully reversed the sleep abnormalities in Tsc1GFAPCKO mice. It restored normal REM sleep levels and normalized the disrupted sleep-wake differentiation between light and dark cycles. This indicates that the sleep problems are dependent on mTOR activation. Rapamycin also reversed the increased orexin expression and cell size in the hypothalamus of these mice.
The study also tested suvorexant, an orexin antagonist, which restored normal REM sleep levels in Tsc1GFAPCKO mice. This suggests that increased orexin contributes to the sleep phenotype in these mice and that targeting the orexin system could be a therapeutic strategy.
In conclusion, this research identifies a novel link between mTOR pathway overactivation and increased orexin expression in the hypothalamus as a key mechanism driving sleep dysfunction in TSC. The findings suggest that both mTOR inhibitors and orexin antagonists could be effective targeted therapies for managing sleep disorders in individuals with tuberous sclerosis complex.
As a follow-up to this study, a recently published paper has identified direct interactions between seizures and sleep in the mouse model that may also involved hypothalamic orexin, with seizures occurring more frequently during sleep and, in turn, REM sleep being further reduced by seizures. Access the follow-up paper here.
Lead author: Michael Wong, MD PhD, Professor of Neurology, Allen P & Josephine B Green Professor of Pediatric Neurology, Professor of Pediatrics, Professor of Neuroscience, Washington University in St. Louis.
Access the paper here.
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