Rapid and Epileptogenic Astrocyte Morphology Changes in the Hippocampus
1 Institute of Cellular Neurosciences, University of Bonn Medical School, Bonn, Germany
2 Institute of Cellular Neurosciences, University of Bonn Medical School, Bonn, Germany. UCL Institute of Neurology, UCL, London, United Kingdom. German Centre for Neurodegenerative Diseases (DZNE), Bonn, Germany.
It is believed that alterations of astrocytes contribute to the onset and maintenance of epileptic activity. These alterations are thought to depend, at least partially, on interactions with the immune system. The contribution of early astrocyte structural responses to epileptiform activity remains to be firmly established. Our laboratory showed that astrocyte morphology in the hippocampus both in vitro and in vivo indeed changes rapidly over minutes after induction of epileptic activity using established epilepsy models. These rapid morphological alterations persist beyond the epileptic activity and increase the probability of further epileptic activity in vitro. We could also reveal that the Rho-associated kinase signalling in astrocytes mediates this effect. However, it is unclear what signalling molecule triggers the astrocyte morphology changes in response to epileptic activity. TNF-alpha is a very promising candidate because it modulates the activity of GTPases of the Rho family in various cell types. Furthermore, increased TNF-alpha levels and seizure susceptibility of hippocampal slices are strongly associated. We therefore study whether exogenous TNF-alpha can rapidly reproduce the fast astrocyte morphology changes in vitro, if these morphology changes promote epileptic activity and if they are mediated by astrocytic TNF-alpha receptors. This is done by established combinations of multiphoton fluorescence microscopy, electrophysiology and pharmacology in acute hippocampal brain slices. Together, these experiments will identify and characterise the currently unknown mechanistic link between epileptic activity and rapid astrocyte morphology changes in the hippocampus.