Human cell-type specific ion dynamics in neuroinflammation and seizures (360G-Wellcome-214042_Z_18_Z)
Epilepsy is more common in Africa than other parts of the world due to high rates of head injuries and infection, which trigger inflammatory processes in the brain. How neuroinflammation causes epilepsy is not well understood. Disruptions in the transmembrane gradient for two key ions: chloride and hydrogen ions, are prototypic features of hyperexcitable neuronal networks. We hypothesize that neuroinflammation affects the cellular regulation of chloride and hydrogen ions, and hence seizure susceptibility in the brain. To test this hypothesis, we will utilize my expertise for measuring ionic changes in the brain together with rare access to human brain tissue donated by patients who have undergone neurosurgical procedures. Our first aim is to establish human brain slice cultures as a model system. We will then transfect different brain cell types with a genetically-encoded chloride and hydrogen ion sensor I have developed in order to generate the first baseline and activity-dependent measurements of these ions in living human neural tissue. Next we will determine how triggering an innate neuroinflammatory response in human brain slice cultures affects circuit excitability and seizure propensity. Finally, we will observe cell-type specific intracellular chloride and pH dynamics during the acute neuroinflammatory response in the human brain.
£94,309 06 Sep 2018