Seizures are the most common neurological symptom in tuberous sclerosis complex (TSC), occurring in 60% to 90% of affected individuals. Yet, it is not clear what goes wrong in the nerve cells (neurons) inside the brain that causes seizures in TSC patients. A loss-of-function change in the DNA sequence of TSC genes leads to an excessive activity of a protein named Rheb. Therefore, we hypothesize that excessive Rheb signaling in TSC disturbs the balance between the excitatory neuron-to-neuron transmission mediated by the amino acid glutamate and the inhibitory neuron-to-neuron transmission mediated by a substance called GABA thus causing seizure activities in TSC. To test our hypothesis, we propose two specific aims: (1) To determine if artificially increasing the amount of Rheb protein in hippocampal neurons alters the amount of AMPA-type glutamate receptors and GABA-A receptors on the surface of neurons, and (2) To determine the effect on the functionality of AMPA-type glutamate and GABA-A receptors. This study of the role Rheb plays in the cell-to-cell transmission will provide the critical rationale for developing therapeutic agents for seizures or even cognitive dysfunction in TSC. If excessive amounts of Rheb in neurons produce an effect similar to the TSC mutations, we can envision identifying small molecules that dampen the functions of Rheb as an effective way to develop new drugs for TSC patients. |
