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 neuropsychiatric symptoms, including epilepsy, intellectual disability, and autism. Sleep disorders are a common occurrence in Tuberous Sclerosis Complex (TSC) and a significant source of decreased quality of life for the patient and family members/caregivers. Furthermore, sleep disturbances, particularly sleep initiation and sleep maintenance insomnia and increased sleep fragmentation (e.g. frequent awakenings from sleep), may exacerbate neurological comorbidities of TSC, such as epilepsy, cognitive dysfunction, behavioral problems, and other psychiatric symptoms. The etiology of sleep disorders in TSC is likely complex and multifactorial, including a variety of environmental, psychosocial, and biomedical factors. Treatment of sleep disorders in TSC is non- specific and often ineffective. From a biomedical standpoint, the existence of comorbid seizures, as well as treatment with antiseizure medications, has been strongly implicated in causing sleep disruption. Independent of seizures, intrinsic dysfunction in sleep circuits and physiology of the TSC brain due to TSC gene mutations may also represent a significant cause or contributor, but minimal clinical or research studies exist that have specifically investigated fundamental biological mechanisms for sleep disorders in TSC. Development of an animal model of sleep disorders in TSC would greatly facilitate mechanistic studies of the neurological basis of sleep dysfunction in TSC, potentially leading to novel targeted therapies for sleep problems in TSC. In this exploratory R21 grant, we propose to develop and characterize a mouse model of sleep disorders in TSC and to identify intrinsic cellular and molecular mechanisms that may underlie sleep disruption. Based on solid preliminary data, we hypothesize that a knockout mouse model of TSC (Tsc1GFAPCKO mice) will exhibit increased sleep fragmentation and other abnormalities of the sleep-wake cycle, independent of seizures. Furthermore, we hypothesize that this sleep fragmentation is related to a mechanistic target of rapamycin (mTOR)-dependent increase in orexin expression in the hypothalamus. This exploratory proposal has strong clinical significance, innovation, and impact, in developing a mouse model of sleep disorders in TSC and identifying cellular and molecular mechanisms for these sleep disorders. These studies may have direct translational applications for developing specific therapeutic options for sleep disorders, including mTOR inhibitors and orexin antagonists.
Public Health Relevance Statement: Sleep disorders are a very common source of morbidity in the general population, leading not only to decreased quality life due to excessive daytime sleepiness and disrupted sleep schedules, but also exacerbating medical co-morbidities, such as behavioral problems, cognitive dysfunction, and epilepsy. Tuberous Sclerosis Complex (TSC) is a common genetic cause of sleep disorders and neuropsychiatric co- morbidities and is often viewed as a model disease that has mechanistic and therapeutic relevance to other developmental brain disorders. The research in this grant aims to develop and characterize a mouse model of sleep disorders in TSC, which should have important clinical and translational applications for investigating mechanisms and identifying novel therapeutic targets for sleep problems in TSC and may also be applicable to sleep dysfunction in other populations.