Temporal lobe epilepsy (TLE) is the most common form of acquired epilepsy, which often results as a consequence of CNS infection and other insults. A high proportion of patients who have developed TLE following encephalitis are often resistant to current anti-seizure drugs (ASDs). As the majority of ASDs target neuronal mechanisms, the role of glial cells in epilepsy is now being actively investigated to identify alternative treatments and disease modifying therapies. The most common pathology associated with TLE, hippocampal sclerosis, involves activation and proliferation of astrocytes that form a glial scar. Astrocytes that comprise the scar have been hypothesized to play an important role in high levels of glutamate found within that tissue. The astrocyte-specific glutamate transporter GLT-1 accounts for approximately 90% of glutamate uptake in the brain. The overall goal of this project is to better understand the contribution of astrocyte-mediated glutamate homeostasis to seizures and to determine if compounds modulating the expression of GLT-1 may act as novel ASDs with potential disease modifying properties. To achieve this goal, we will conduct multidisciplinary experiments in the Theiler?s Murine Encephalomyelitis Virus (TMEV) mouse model of infection-induced TLE. This animal model, the first infection induced model of TLE, recapitulates clinical observations including neurodegeneration, formation of a glial scar, and the development of spontaneous seizures.
Aim 1 will investigate changes in GLT-1 expression in reactive and glial scar astrocytes following TMEV infection. The use of electrophysiology in combination with immunoblot techniques is a superior way to observe functional alterations in glutamate regulation during the acute seizure phase in TMEV infected animals.
Aim 2 will determine if a modulator of GLT-1 expression can be used as a tool to manipulate glutamate transmission and ameliorate neurotoxicity following TMEV infection. Ceftriaxone (CEF) is a safe and commonly used ?-lactam antibiotic that has been shown to increase GLT-1 expression and prevent neuronal injury in other animal models of neurological disease. Thus, conducting these experiments will provide an outstanding training environment and determine the role of GLT-1 modulation in a clinically relevant epilepsy model. Additionally, the proposed experiments may provide valuable information for future disease modifying therapies for the patient with CNS infections that could lead to epilepsy.
PROJECT NARRITIVE Maintaining neurotransmitter homeostasis in the brain is critical for proper brain function. Determining whether cells responsible for maintaining glutamate levels play a role in the pathogenesis of epilepsy is essential for understanding the basis of the disease and developing more effective therapies.
