Final Report Summary - HEP (Epilepsies of the temporal lobe: emergence, basal state and paroxysmal transitions)
This project examined the natural history of human epilepsies. Using living tissue obtained after operations on epileptic patients and animal tissue, we asked: How does an epileptic brain emerge? What are its basal properties? What changes occur during a seizure?
On the emergence, we showed changes in the homeostasis of lipids, including fatty acids and cholesterol, were associated with neuronal death, a critical precursor of some epilepsies.
We developed a useful technique to study the emergence of epilepsies. We can now keep epileptic human tissue alive in culture over several weeks. Viral transfection of optical probes lets us image critical aspects of single cell function. Signals of activity from many neurons lets us see how epileptic activity begins and spreads.
On the basal properties, of an epileptic brain, we identified mutations were identified in an inherited epilepsy gene, DEPFC5, which results in focal malformations and seizures in the cortex. We also used RNA analysis of human tissue to obtain a complete view of molecular changes in regions of an epileptic brain with high or low levels of neuronal loss.
On the transition to a seizure, we showed epileptic activities generated by tissue around cortical tumors results from defects in control of the brain ionic milieu similar to those operating in medial temporal lobe epilepsy. With RNA-seq analysis we showed many molecules activated by a human seizure have an immune function. We confirmed one of them, the human interleukin-8, was released by inducing an artificial seizure in tissue slices.
These data led to work on human microglia, brain-resident immune cells. We find they respond differently to equivalent cells in lab-animals when exposed to molecules signaling cellular activity and damage.
Overall, these differences suggest human diseases may be best studied with human tissue.
On the emergence, we showed changes in the homeostasis of lipids, including fatty acids and cholesterol, were associated with neuronal death, a critical precursor of some epilepsies.
We developed a useful technique to study the emergence of epilepsies. We can now keep epileptic human tissue alive in culture over several weeks. Viral transfection of optical probes lets us image critical aspects of single cell function. Signals of activity from many neurons lets us see how epileptic activity begins and spreads.
On the basal properties, of an epileptic brain, we identified mutations were identified in an inherited epilepsy gene, DEPFC5, which results in focal malformations and seizures in the cortex. We also used RNA analysis of human tissue to obtain a complete view of molecular changes in regions of an epileptic brain with high or low levels of neuronal loss.
On the transition to a seizure, we showed epileptic activities generated by tissue around cortical tumors results from defects in control of the brain ionic milieu similar to those operating in medial temporal lobe epilepsy. With RNA-seq analysis we showed many molecules activated by a human seizure have an immune function. We confirmed one of them, the human interleukin-8, was released by inducing an artificial seizure in tissue slices.
These data led to work on human microglia, brain-resident immune cells. We find they respond differently to equivalent cells in lab-animals when exposed to molecules signaling cellular activity and damage.
Overall, these differences suggest human diseases may be best studied with human tissue.