Modulation of astrocytic gap junction coupling in focal epilepsy

Understanding the mechanisms that underlie epileptogenesis is crucial for the development of new treatments. Recent evidence has implicated astrocytes as a key cell population in the aetiology of focal epilepsy.

Astrocytic gap-junction networks perform vital functions in supporting neural activity, including the shuttling of essential metabolic fuels and the regulation of the extracellular ionic environment for neurons.

The objective of this project is to understand the relationship between neuronal activity and astrocytic gap-junction coupling, and how this relationship may break down in epilepsy.

This will build upon preliminary evidence that astrocytic gap-junctions can show rapid, activity-dependent changes, in a manner related to levels of neuronal activity.

The work will use surgically-resected human brain tissue and mouse models in which it is possible to selectively manipulate defined cell types. There are three parallel research aims.

First, glioma-associated brain tissue will be used as a test case to relate functional astrocytic gap-junction coupling and neuronal hyperexcitability in a human context.

Second, in vivo optical studies in mouse will examine how epileptiform network activity influences dynamic astrocytic gap-junction coupling.

And third, optogenetic and pharmacological strategies will be used to dissect the cellular mechanisms that mediate activity-dependent changes in astrocytic coupling.