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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS056872-07
Application #
8440312
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Mamounas, Laura
Project Start
2006-08-21
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
7
Fiscal Year
2013
Total Cost
$314,445
Indirect Cost
$107,573
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Zhang, Bo; Zou, Jia; Han, Lirong et al. (2018) The specificity and role of microglia in epileptogenesis in mouse models of tuberous sclerosis complex. Epilepsia 59:1796-1806
Griffith, Jennifer L; Wong, Michael (2018) The mTOR pathway in treatment of epilepsy: a clinical update. Future Neurol 13:49-58
Jeong, Anna; Wong, Michael (2018) Targeting the Mammalian Target of Rapamycin for Epileptic Encephalopathies and Malformations of Cortical Development. J Child Neurol 33:55-63
Jeong, Anna; Nakagawa, Jo Anne; Wong, Michael (2017) Predictors of Drug-Resistant Epilepsy in Tuberous Sclerosis Complex. J Child Neurol 32:1092-1098
Zou, Jia; Zhang, Bo; Gutmann, David H et al. (2017) Postnatal reduction of tuberous sclerosis complex 1 expression in astrocytes and neurons causes seizures in an age-dependent manner. Epilepsia 58:2053-2063
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Wong, Michael (2016) Commentary: mTOR inhibition suppresses established epilepsy in a mouse model of cortical dysplasia. Epilepsia 57:1349-50
Jeong, Anna; Wong, Michael (2016) Systemic disease manifestations associated with epilepsy in tuberous sclerosis complex. Epilepsia 57:1443-9
Guo, Dongjun; Zeng, Linghui; Zou, Jia et al. (2016) Rapamycin prevents acute dendritic injury following seizures. Ann Clin Transl Neurol 3:180-90

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