Tuberous Sclerosis Complex (TSC) is one of the most common genetic causes of epilepsy. In addition, epilepsy in TSC is typically very severe and intractable to available therapies. Most current treatments for epilepsy are simply symptomatic therapies that may suppress seizures but do not necessarily correct the underlying brain abnormalities causing the epilepsy. Thus, understanding the brain mechanisms causing epilepsy (""""""""epileptogenesis"""""""") is necessary to develop more effective, """"""""anti-epileptogenic"""""""" treatments for both TSC and non-TSC-related epilepsy. We have previously described a mouse model of TSC that recapitulates many features of human TSC (Tsc1GFAPCKO mice), including severe epilepsy. In the first funding period of this grant, we have described a number of cellular and molecular abnormalities in glia and neurons that contribute to epileptogenesis in these mice, such as astrocyte proliferation, neuronal death, impaired glial buffering of neurotransmitters and potassium ions, and abnormal regulation of specific cell signaling pathways. Most remarkably, we showed that pharmacological inhibition of one of these signaling pathways, the mammalian target of rapamycin (mTOR) pathway, completely prevented the development of epilepsy in Tsc1GFAPCKO mice, representing one of the first demonstrations of a robust anti-epileptogenic effect in any epilepsy model. In this grant renewal application, we propose to extend our previous work, now further characterizing specific TSC-regulated signaling pathways involved in epileptogenesis. Our general hypothesis is that epileptogenesis results primarily from initial abnormalities in specific cell signaling pathways and correction of these signaling abnormalities may prevent epileptogenesis in Tsc1GFAPCKO mice, as well as in other epilepsy models. Findings from this grant should help identify novel mechanisms of epileptogenesis and identify new anti- epileptogenic therapeutic approaches not only for epilepsy in TSC, but potentially for all epilepsy in general.

Public Health Relevance

Epilepsy affects ~1-2% of all people and is associated with increased mortality, as well as significant neurological morbidity, such as memory difficulties, learning disabilities, and mental retardation. The research in this grant aims to determine mechanisms of epileptogenesis in Tuberous Sclerosis Complex, one of the most common genetic causes of epilepsy, as well as in other models of epilepsy, and to develop novel """"""""anti- epileptogenic"""""""" therapeutic approaches that do not just suppress seizures but actually correct the underlying brain abnormalities causing epilepsy. Thus, given the high prevalence of epilepsy in the general population, this research has strong relevance to public health and has the potential to have a significant positive impact in improving public health.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Morris, Jill A
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Washington University
Schools of Medicine
Saint Louis
United States
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Guo, Dongjun; Zeng, Linghui; Zou, Jia et al. (2016) Rapamycin prevents acute dendritic injury following seizures. Ann Clin Transl Neurol 3:180-90
Wong, Michael (2016) Commentary: mTOR inhibition suppresses established epilepsy in a mouse model of cortical dysplasia. Epilepsia 57:1349-50
Wong, Michael; Roper, Steven N (2016) Genetic animal models of malformations of cortical development and epilepsy. J Neurosci Methods 260:73-82
Zhang, Bo; Zou, Jia; Han, Lirong et al. (2016) Microglial activation during epileptogenesis in a mouse model of tuberous sclerosis complex. Epilepsia 57:1317-25
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Rensing, Nicholas; Han, Lirong; Wong, Michael (2015) Intermittent dosing of rapamycin maintains antiepileptogenic effects in a mouse model of tuberous sclerosis complex. Epilepsia 56:1088-97
Zhang, Bo; Zou, Jia; Rensing, Nicholas R et al. (2015) Inflammatory mechanisms contribute to the neurological manifestations of tuberous sclerosis complex. Neurobiol Dis 80:70-9
Lu, Zhenya; Liu, Furong; Chen, Linglin et al. (2015) Effect of Chronic Administration of Low Dose Rapamycin on Development and Immunity in Young Rats. PLoS One 10:e0135256
Wong, Michael (2013) Mammalian target of rapamycin (mTOR) activation in focal cortical dysplasia and related focal cortical malformations. Exp Neurol 244:22-6
Wong, Michael (2013) A critical review of mTOR inhibitors and epilepsy: from basic science to clinical trials. Expert Rev Neurother 13:657-69

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