Epilepsy represents one of the most devastating complications of tuberous sclerosis complex (TSC) in children. Affecting nearly 80' of children with TSC, these seizures are often unresponsive to standard anti-epileptic medications and therefore result in significant morbidity and mortality. Despite recent advances in our understanding of the molecular biology of the TSC gene products, tuberin and hamartin, there is relatively little known about the role of these genes in the pathogenesis of epilepsy. Our ability to design tailored therapies for the seizures in TSC is heavily dependent on a more detailed understanding of the genetic and cellular abnormalities that result from TSC gene dysfunction in the brain, as well as the generation of accurate in vitro and in vivo models of TSC-related epilepsy. The experiments proposed herein are directed at determining the mechanism by which Tsc1 inactivation in one cell type in the brain (astrocytes) results in abnormal neuronal organization and excitability that culminate in seizures.

To determine how defects in TSC gene function in the brain result in seizures, we have generated mice in which the Tsc1 gene is selectively inactivated in astrocytes. As a result of astrocyte-specific Tsc1 inactivation, these mice develop increased astrocyte growth, abnormal neuronal organization, and electro-encephalographically (EEG)-proven seizures. Using this potential preclinical model of TSC-associated epilepsy, we propose to define the critical cellular and genetic parameters that culminate in seizures.

In this proposal, we plan to test the hypothesis that (1) astrocyte-specific Tsc1 inactivation results in abnormal neuronal migration due to disrupted cellular interactions between astrocytes and neurons, and (2) increased neuronal excitability is a consequence of decreased astrocyte clearance of excitatory neurotransmitters. The experiments proposed in this study are aimed at characterizing critical cellular and genetic changes in the brain resulting from astrocyte-specific Tsc1 inactivation that lead to the development of epilepsy. Using this potential preclinical model of TSC-related epilepsy, we are in the unique position to determine how seizures develop in children with TSC. The insights that derive from this study may allow the design of future tailored therapies for TSC-related epilepsy.