Prolonged continuous seizure activity (status epilepticus, SE) is associated with an increased risk for developing epilepsy with hippocampal sclerosis and comorbidities such as long-term cognitive impairments. The molecular mechanisms underlying these changes following SE are not well-understood. In experimental models, SE triggers immediate and long-lasting dysregulation of the mammalian target of rapamycin (mTOR) pathway, which has been implicated in epileptogenesis. Under physiological conditions mTOR modulates dendritic morphology and ion channels, synaptic plasticity, and memory, but the role of mTOR in behavioral deficits following SE has not been evaluated. Previously it has been shown that excessive activation of the mTOR pathway in transgenic rodents is associated with behavioral deficits, seizures, mossy fiber sprouting, and dendritic abnormalities, which are reversed following treatment with the mTOR inhibitor, rapamycin. Based on these studies, we hypothesize that mTOR pathway dysregulation contributes to the morphological and molecular alterations in hippocampal dendrites and the associated hippocampal-dependent learning and memory deficits that occur following SE. We have pilot data demonstrating that treatment with rapamycin improves dendritic morphology and ion channel dysregulation and rescues hippocampal- dependent spatial learning and memory deficits early following SE. Our pilot data also suggest that the rescue of the behavioral phenotype is not sustained as the effect does not last into the period of chronic epilepsy. Thus, transient rapamycin therapy is not sufficient to block long-term alterations in behavior following SE, suggesting that chronic treatment with rapamycin or more potent mTOR inhibitor therapy may be required. In the studies proposed here we will further evaluate changes in the downstream signaling of mTORC1 and 2 following SE. Furthermore, we will investigate whether translation rates are altered following SE. To this end, we will employ polysome profiling and monitor the effectiveness of PP242 compared to rapamycin. We will use inhibitor regimens that include early and late treatments following SE. We will use biochemistry, dendritic morphological assessments, behavior, and electroencephalography as outcome measures. Since these inhibitors are already in use clinically or are being extensively studied and developed in oncology, there is the potential to rapidly translate to treatments for epilepsy and comorbidities in humans.
The aims of this proposal are as follows: 1) To further characterize aberrant mTOR signaling and evaluate dysregulation of mTORC1- dependent mRNA translation following SE;2) To evaluate whether mTOR pathway dysregulation contributes to dendritic structural and molecular alterations following SE;3) To evaluate whether mTOR pathway dysregulation contributes to learning and memory deficits that occur following SE;and 4) To compare the effect of rapamycin versus PP242 on epileptiform activity.
There is growing evidence that the mammalian target of rapamycin pathway contributes to epilepsy. Inhibitors of the pathway already in clinical use for other disorders may provide candidate novel therapies with rapid translation to the treatment of epilepsy. We will pursue this possibility in the proposed studies.
|Nguyen, Lena H; Brewster, Amy L; Clark, Madeline E et al. (2015) mTOR inhibition suppresses established epilepsy in a mouse model of cortical dysplasia. Epilepsia 56:636-46|