Epilepsy patients often experience cognitive deficits, such as memory problems, learning disabilities, and mental retardation. Although environmental and psychosocial factors can also affect brain function, there has been increasing focus on the role of seizures themselves in damaging the brain and thus causing further neurological deficits and decline in epilepsy patients, as well as progressively worsening seizures. Seizures can potentially injure the brain by a variety of mechanisms, including the death of neurons. However, since many people with epilepsy do not have obvious structural evidence of neuronal death on brain imaging or pathological studies, "non-lethal" effects of seizures on the structure and function of synapses and dendrites, the critical sites where neurons communicate, may be equally important in causing brain dysfunction in epilepsy patients. In our previous work, our lab has utilized cutting-edge imaging techniques to directly visualize in living mice injury to dendrits caused by seizures. In this project, we propose to address the hypothesis that a specific cell signaling pathway, called the mammalian target of rapamycin (mTOR) pathway, is involved in causing seizure-induced dendritic injury. First, we will use in vivo multiphoton imaging techniques to visualize whether inhibiting the mTOR pathway can prevent seizure-induced dendritic injury. Next, we will determine whether the mTOR pathway has neuroprotective effects on dendrites by regulating other cellular pathways and molecules related to the actin cytoskeleton of dendrites. Finally, we will investigate the physiological and functional consequences of seizure-induced dendritic injury related to cortical processing of sensory information in mice and test the ability of mTOR inhibitors to preserve normal function. This project should lead to important insights into the detrimental effects of seizures on dendrites and may ultimately lead to novel therapeutic approaches for preventing cognitive deficits and other neurological consequences of epilepsy.
Epilepsy affects ~1-2% of all people and is associated with increased mortality, as well as significant neurological morbidity, such as memory difficulties, learning disabilities, and mental retardation. The research in this grant aims to determine mechanisms of seizure-related brain injury and may ultimately lead to novel treatments to prevent or alleviate neurological deficits in epilepsy patients. Thus, given the high prevalence of epilepsy in the general population, this research has strong relevance to public health and has the potential to have a significant positive impact in improving public health.
|Wong, Michael (2013) A critical review of mTOR inhibitors and epilepsy: from basic science to clinical trials. Expert Rev Neurother 13:657-69|