The phosphoinositide 3-kinase/mammalian target of rapamycin signaling cascade (hereafter referred to as the mTOR cascade) is a universal regulator of cell growth, survival and proliferation. These processes are regulated via mTOR interactions with the Raptor (regulatory associated protein of mTOR) protein, which leads to activation of mTOR complex 1 (mTORC1). mTORC1 controls neuronal cell growth and dendritic protein synthesis by phosphorylating downstream targets leading to a net result of de novo RNA translation. mTORC1 signaling is hyperactivated in genetic and acquired epilepsies in humans and animal models. Our lab and others have shown that mTORC1 is altered early following prolonged chemoconvulsant-induced seizures [status epilepticus (SE)] in rodents. In these models, the animals subsequently develop epilepsy and express dendritic alterations such as the disruption of cytoskeletal proteins like microtubule-associated protein-2 (MAP2) and aberrant potassium channel expression. We propose that these changes contribute to spontaneous seizures and memory deficits observed in epilepsy. mTORC1 regulates these aspects of dendrites under physiological conditions, suggesting that hyperactivation of mTORC1 signaling may promote epilepsy and the associated learning and memory deficits, at least, in part, through dysregulation of dendritic function and ion channel expression.
The aims of this research proposal are: 1) to further characterize aberrant mTOR signaling in the pilocarpine model of epilepsy and evaluate mTORC1 inhibition using rapamycin 2) to evaluate whether mTOR hyperactivity contributes to dendritic abnormalities in this model, and 3) to evaluate whether mTOR hyperactivity contributes to the hippocampal-dependent behavioral deficits observed in epilepsy. We will employ a series of biochemical, pharmacological, neurophysiological and behavioral assays for these studies.
The mammalian target of rapamycin cascade (mTOR) is abnormally activated in some forms of acquired and genetic epilepsy. Current research in acquired epilepsy has implicated mTOR signaling immediately following acute seizure onset, however its role in epilepsy is not well defined. The purpose of this research is to investigate th role of mTOR in epilepsy and by understanding this pathway novel therapeutic strategies may result that can be applied to treating epilepsy.