Neurological disorders such as seizure are very common in tuberous sclerosis complex (TSC) and affect about 80% to 90% of the patients during their lifetime. However, the mechanisms for the neurological symptoms remain unknown. Recently, mutations within the two relevant genes, TSC1 and TSC2, were identified for their association to the onset of the disease. The target of these gene products is a small GTPase, Rheb. Interestingly, Rheb was first identified for its induced expression profile in a seizure model and is highly expressed in the brain. The long-term goal of this program is to understand how the TSC1/2 signaling pathway is involved in the neurological disorders in TSC. Our approach is to identify and study the effectors of Rheb and their role in these disorders. Our recent work has suggested that there is a novel interaction between Rheb and a synaptic vesicle protein, SV2A, that is highly expressed in the brain with unidentified function. Importantly, inactivation of SV2A causes severe seizure and further death of the affected mice. Furthermore, SV2 was also identified as a binding target for a new anti-seizure drug, levetiracetam, thereby reinforcing its role in seizure production. Our proposed experiments aim at characterizing the interaction and examine how Rheb regulates SV2 function at the level of neuronal communication, namely synaptic transmission. This study will not only help to understand a role of TSC1/2-Rheb in neurological disorders but also provide critical information for drug design for TSC-specific neurological disorders, including epilepsy.