Neurological complications, such as epilepsy, mental retardation, and autism, represent common sources of significant morbidity and mortality in children with tuberous sclerosis complex (TSC). Epilepsy, in particular, can be especially devastating and is often refractory to available treatments. Understanding the molecular, biochemical, and physiological mechanisms underlying epileptogenesis in TSC is critical to the development of more effective therapies for seizures in patients with TSC. Seizures and other neurological symptoms of TSC reflect the presence of characteristic developmental brain abnormalities, such as cortical tubers. Cortical tubers contain abnormally differentiated neuroglial cells and excessive gliosis, suggesting that glial cells may be important in the pathophysiology of epilepsy and brain dysfunction in TSC. To understand the contribution of glial cells to TSC brain dysfunction, we developed a novel mouse model of TSC (Tsc1[GFAP]CKO mice), in which Tsd inactivation in glia results in abnormalities in glial growth, proliferation, and differentation, neuronal disorganization, and severe epilepsy. The primary goal of this proposal is to elucidate the molecular, biochemical, and electrophysiological mechanisms by which glial defects in Tsd lead to seizures in Tsc1[GFAP]CKO mice. We hypothesize that glial Tsd inactivation results in impaired uptake of glutamate and potassium by astrocytes, which may promote epileptogenesis by causing abnormal extracellular glutamate and potassium homeostasis, excitotoxic neuronal death, and hyperexcitable neuronal circuits. In this project, we propose to determine the effects of glial Tsd inactivation on 1) the expression and function of specific astrocyte glutamate transporters and potassium channels, 2) extracellular glutamate and potassium levels, 3) induction of excitotoxic neuronal death, and 4) neuronal excitability on both the single cell and circuit levels in Tsc1[GFAP]CKO mice. Furthermore, the involvement of specific cellular signaling pathways, previously implicated in TSC, in mediating these effects will be investigated. In these studies, we will employ a unique combination of molecular genetic, biochemical, and electrophysiological approaches in the context of a successful, synergistic collaboration between two independent research laboratories to address these critical issues. In addition to defining the cellular and molecular mechanisms causing seizures specifically in TSC, these studies should provide broader insights into the general role of glial cells in epileptogenesis and identify novel therapies for seizures directed at astrocytes that may benefit all patients with epilepsy. Since epilepsy affects approximately 1% of all people, this research has the potential to have significant impact on public health. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS056872-03
Application #
7487849
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Fountain, Jane W
Project Start
2006-08-21
Project End
2010-05-14
Budget Start
2008-08-01
Budget End
2010-05-14
Support Year
3
Fiscal Year
2008
Total Cost
$259,058
Indirect Cost
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
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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
Wong, Michael (2016) Commentary: mTOR inhibition suppresses established epilepsy in a mouse model of cortical dysplasia. Epilepsia 57:1349-50
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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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