The mechanistic target of rapamycin (mTOR) signaling network plays a crucial role in cellular function, integrating information provided by growth factors, nutrient availability and synaptic input to regulate processes such as synthesis of macromolecules, energy metabolism and growth. Properly balanced mTOR signaling has proven to be particularly important in the brain, where mutations or deletions in several genes that code for proteins that regulate mTOR function are associated with autism, intellectual disability and epilepsy in humans and mouse models. Despite the strong link between the mTOR pathway and neurological disease, the mechanisms that lead from the genetic defects to phenotypes are still unknown. My previously published and preliminary data show that hyperactive mTOR signaling leads to altered synaptic transmission. Since changes in synaptic transmission can generate the altered network activity that results in neurological disorders, and especially seizures, this represents a possible mechanistic link between pathological mTOR activation and epilepsy. The scientific aims of this research plan are to better understand: 1) th regulation of synaptic transmission and connectivity by the mTOR signaling cascade, 2) the molecular events that mediate mTOR's effect on synaptic function, 3) how neurons that have altered mTOR signaling affect the function of the neural circuits in which they operate and 3) how these changes lead to network synchronizations that underlie epilepsy. The achievement of these objectives requires the integration of molecular, cellular and network-level approaches including: 1) electrophysiological analysis of synaptically connected, genetically-modified neuron pairs, 2) quantitative imaging of cellular and subcellular structures, 3) two-photon multicellular calcium imaging and electrophysiological analysis of hippocampal microcircuits. Although I already possess the skills necessary to implement the first two approaches, I require additional training from my mentor and co-mentor to carry out the circuit- level analysis. Two years of mentored support at the Jan and Dan Duncan Neurological Research Institute at Baylor College of Medicine will allow me to learn these techniques, develop professional skills, and generate additional publications I need to secure a tenure-track faculty position. Successful completion of this project will provide unparalleled insight into the regulation of synaptic and circuit functionby the mTOR signaling network and identify potential targets for treatment of mTOR-related diseases. It will also establish a rigorous framework to test the effects of other neurological disease-causing genes on neuronal function, and an excellent start to a career leading an independent research program.
I am proposing to study a gene (Pten) and pathway (mTOR) whose dysfunction causes epilepsy and other neurological disorders in humans. The results will identify new molecules, and therefore potential drug targets, that mediate the effects of these gene mutations on neuronal function. They will also provide new insights into the functional changes to neuronal networks that accompany the disease state.