There are currently no effective therapies for preventing epilepsy in at-risk patients. The mammalian target of rapamycin (mTOR), however, has emerged as a promising molecular target for the development of disease-modifying therapies. mTOR regulates a wide range of cellular processes through the signaling complexes mTORC1 and mTORC2. mTORC1 signaling is enhanced in chemical, injury-induced and genetic models of epilepsy, implying that the pathway could be involved in many different forms of the disease. Blocking mTOR signaling with the mTOR antagonist rapamycin appears to have anti-epileptogenic effects. Conversely, genetically enhancing mTOR signaling by deletion of upstream inhibitors produces spontaneous seizures in mice. Recent work from our lab further demonstrates that deletion of the mTOR inhibitor PTEN need only occur in a subset of newborn hippocampal dentate granule cells (DGCs) to produce the disease. PTEN knockout DGC developed the hallmark pathologies of the epileptic brain, including axon sprouting, ectopic cell migration and aberrant dendrite formation. The recurrent excitatory connections formed by pathological DGC are believed to destabilize the hippocampal circuit, promoting hyperexcitability and seizures. Despite clear evidence that dysregulation of the mTOR pathway can cause epilepsy in animals models and a small number of genetic epilepsy conditions in humans, however, the evidence that mTOR mediates epileptogenesis in acquired epilepsy syndromes is based entirely on correlational evidence and studies with the drug rapamycin and its analogs. Rapamycin is presumed to inhibit epileptogenesis by acting on mTORC1, and the site of action is presumed to be neurons; but these assumptions have not yet been experimentally proven. We hypothesize that in temporal lobe epilepsy, mTORC1 hyperactivation among newborn DGCs causes these neurons to integrate abnormally, and that these abnormal cells promote epileptogenesis. We also propose the alternate hypothesis, that mature hippocampal and cortical neurons drive epileptogenesis. To assess the role of mTOR activation in different neuronal populations, we will use conditional, inducible transgenic mouse strategies to delete mTOR from newborn granule cells or forebrain neurons. To test the role of different mTOR pathway members, we will delete the mTORC1 and mTORC2 adaptor proteins raptor and rictor, respectively. Finally, to determine whether the findings can be generalized, studies will be conducted in three different models of epilepsy. Together, these studies will reveal critical neuronal populations and identify druggable targets for the development of anti-epileptogenic therapies.
There are currently no treatments that can prevent the development of epilepsy in at-risk patients. Recent studies, however, suggest that antagonists of the mTOR pathway, which regulates neuronal plasticity and growth, might be useful candidates. The proposed studies will determine whether mTOR signaling is the correct target for anti-epileptogenic therapies, and if so, where in the brain the pathway has to be inhibited to prove effective. These studies are aimed at guiding the development of the first ever anti-epilepsy therapies.
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