Infantile spasms (IS) is a specific epilepsy syndrome of infancy that is typically associated with a poor long-term neurological prognosis, including intellectual disability, autism, and chronic epilepsy. Some treatments are available for IS, such as adrenocorticotrophin and vigabatrin, but despite treatment, many patients have refractory IS or go onto to develop other seizure types and the associated chronic neurological disabilities. Developing better therapies for IS depends on having a good understanding of the underlying pathophysiological mechanisms of IS. There are numerous acquired and genetic causes of IS, suggesting that IS is a ?final common pathway? in response to various brain injuries or defects at this particular stage of brain development. Tuberous sclerosis complex (TSC) is a relatively common genetic developmental brain disorder and represents one of the most common genetic causes of IS. Conversely, IS has a high prevalence in TSC, occurring in about one-third of all TSC patients. Furthermore, IS is a risk factor for long-term neurological sequelae, such as intellectual disability, autism, and drug-resistant epilepsy in TSC. Recent advances have provided insights into the pathophysiology of the neurological manifestations of TSC, particularly the involvement of the mechanistic target of rapamycin (mTOR, or mTORC1) pathway, and raised the possibility of potential disease-modifying therapies in TSC, such as with mTOR inhibitors. In addition, vigabatrin (VGB) is a uniquely effective treatment for IS in TSC, but, despite being a known GABA modulator, the precise mechanism of action of VGB against IS in TSC is not clear. Development and characterization of an animal model of IS in TSC would facilitate mechanistic studies and potential therapeutic applications, which could have impact not just for TSC, but IS due to other causes. In this exploratory R21 grant, the specific aims are to develop a mouse model of IS in TSC, involving either spontaneous or induced spasm-like seizures in a knock- out mouse model of TSC (Tsc1GFAPCKO mice) that is known to have epilepsy and cognitive deficits later in life. Video-EEG will be performed in pre-weanling Tsc1GFAPCKO mice between postnatal days 10 to 18 to monitor for spontaneous spasms and EEG abnormalities. In addition, a ?two-hit? model of TSC will be generated by combining application of N-methyl-D-aspartate (NMDA) or lipopolysaccharide (LPS), which can induce spasms in control mice, with the genetic defect of Tsc1 inactivation in Tsc1GFAPCKO mice. Effects of vigabatrin and rapamycin will also be assessed. Successful development of a model of IS in TSC has strong future clinical and translational applications for investigating mechanisms and identifying novel therapeutic targets for IS in TSC, such as understanding the unique efficacy of vigabatrin and the potential mechanisms downstream from mTOR.
Public Health Relevance Statement: Infantile spasms (IS) is a developmental epilepsy syndrome of infancy due to a variety of genetic and acquired causes and is strongly associated with a poor long-term neurological prognosis, including intellectual disability, autism, and chronic epilepsy. Tuberous Sclerosis Complex (TSC) is a common genetic cause of IS 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 a novel animal model of IS in TSC, which should have important future clinical and translational applications for investigating mechanisms and identifying novel therapeutic targets for IS.
