Temporal lobe epilepsy (TLE) is a seizure disorder that may arise months to years after certain brain injuries. Once developed, TLE is difficult to treat. A current NIH benchmark for epilepsy research includes a better understanding of why patients develop TLE. Towards that end, epilepsy researchers must understand the role of non-electrical cell types in the brain, like the astrocyte, in the epilepsy development process. Astrocytes have the ability to directly alter neuronal transmission. Seizures result from the synchronous activation of a population of neurons. Understanding the mechanisms that astrocytes utilize to sense and manipulate neuronal activity may uncover new therapies to dampen neuronal activity and reduce seizures. The overall goal of the project is to better understand the downstream activity of a receptor which emerges on the astrocyte in multiple animal models of TLE. This receptor, known as mGluR5, represents a means for the astrocyte to sense neuronal activity. In response to neuronal activity, mGluR5 promotes increased calcium activity in the astrocyte. However, the potential consequences of astrocyte calcium activity in TLE are not well understood.
A first aim will determine which stages of TLE development could be impacted by astrocyte mGluR5 activity. Imaging the calcium activity in astrocytes downstream of mGluR5 activation can give an indication of when this pathway is functional during TLE development.
A second aim will investigate a potential consequence of astrocyte mGluR5 activity. One suggested outcome of astrocyte mGluR5 activity is the closer physical enwrapping of neuronal synapses by the astrocyte. The potential impact of greater physical enwrapping includes a heightened ability of astrocytes to sequester neuronal glutamate, once released. In effect, this heighted glutamate sequestration could reduce excitability and represent a natural response of the brain to injury. Greater physical enwrapping can be observed with high-resolution electron microscopy techniques. An important question is whether the benefits of enwrapping persist after injury. If response mechanisms like enwrapping fail to continue after injury, it may help to explain why patients can develop epilepsy months to years after injury.
Physical interactions between cells in the brain are critical for proper brain function. Determining how and why cells interact differently in the brain following injury is an important component in determining why patients develop diseases and disorders like epilepsy.
