Tuberous sclerosis complex (TSC) is a genetic disease characterized by neurological problems, such as epilepsy and intellectual disability, and by tumor susceptibility. The disease is due to the loss of either the Tsc1 or the Tsc2 gene. These genes produce proteins that form a complex that inhibits a well-known growth-promoting factor named mTOR. Thus, loss of the TSC complex results in excessive mTOR activity, leading to tumor growth and likely responsible for epilepsy. However, it is not clear whether this mechanism underlies cognitive dysfunction in TSC patients. Recent studies in mice have shown that loss of Tsc2 also results in the increase expression of Pten, another tumor-suppressor gene that works upstream of mTOR. We have discovered that Pten binds to and affects the expression of the NMDA receptor, a neurotransmitter receptor that is very important for learning and cognition. Thus, it is possible that changes in this receptor may underlie cognitive dysfunction in tuberous sclerosis patients.

In this proposal, I hypothesize that loss of Tsc2 causes changes in NMDA receptor expression that are mediated by alterations in Pten through direct protein-protein interactions, and not by changes in mTOR signaling.

To test my hypothesis, we will use genetically modified mouse models that are deficient in either Pten or Tsc2. In Specific Aim 1, we will examine and compare the expression of several subunits that form the NMDA receptor in the two mouse lines. In Specific Aim 2, we will conduct genetic and pharmacological experiments to determine whether changes in NMDA receptor that occur in Tsc2 mutant mice are due to the activity of Pten or that of mTOR.

This proposed work is highly innovative because, despite its importance for cognition, very little is known about NMDA receptor regulation in tuberous sclerosis patients or in animal models of the disease. So far, most studies on tuberous sclerosis have focused on the role of mTOR, whereas this study explores alternative possibilities that may reveal a novel mechanism of disease. For example, our studies may show that changes in Pten levels, rather than those of mTOR activity, are crucial to the alteration in NMDA receptor expression and lead to cognitive problems. If this is the case, future studies can be designed to restore normal receptor activity through pharmacological manipulations of the receptor or pharmacological inhibition of Pten in animal models. Concurrently, studies using human tissue can be conducted using brain biopsies derived from patients with tuberous sclerosis complex to determine whether abnormalities similar to those observed in mouse models are present. If this is the case, Pten inhibitors or NMDA receptor antagonists may be evaluated as novel therapies to improve cognition defects in TSC patients. These novel strategies may ultimately lead to an improvement of the neurological symptoms of tuberous sclerosis.