A team of researchers led by the Institute of Cellular Neurosciences at the University of Bonn has discovered a new cause to explain the development of temporal lobe epilepsy. At an early stage, astrocytes are uncoupled from each other.
This results in the extracellular accumulation of potassium ions and neurotransmitters, which cause hyperexcitability of the neurons.
Approximately two percent of the population suffers from epilepsy, and approximately one-third of patients are therapy-resistant. Said Prof. Dr. Christian Steinhäuser:
“Despite intense research efforts, the causes of this disease are still largely unclear. In some frequent forms such as temporal lobe epilepsy, this percentage is even significantly higher."
So scientists are searching for new strategies in epilepsy research to develop new, more efficient therapeutic approaches.
One such new approach in the research into causes of epilepsy has now been found by a team working with Prof. Steinhäuser.
Together with neurosurgeons from the University of Bonn Hospital as well as epilepsy specialists from the Freiburg University Hospital, the Institute of Cellular Neurosciences of the University of Bonn investigated the functional properties of astrocytes. These are nervous system cells which belong to the glial cells.
They were originally considered only to be “glue” holding the brain together, but in recent years, astrocytes have increasingly turned out to be an important partner to neurons.
“Epilepsy research is dominated by the assumption that altered properties of neurons cause epilepsy,” says Prof. Steinhäuser.
Steinhäuser’s team has now shown that malfunctions of glial cells play a crucial role in the development of epilepsy. Brain tissue removed from patients with temporal lobe epilepsy was observed by the researchers to be completely lacking in astrocytes.
“In this condition, no functional networks of coupled astrocytes can be formed,” says first author Dr. Peter Bedner.
Hyperexcitability of Neurons
Because astrocytic networks are missing, potassium ions and neurotransmitters, such as glutamate, which are important for signal transmission, can accumulate in this tissue. This leads to hyperexcitability of the affected neurons and ultimately to epileptic seizures.
Is the loss of astrocytic coupling the cause of epilepsy or is this merely a consequence of hyperexcitability?
To be able to address this question, the scientists specifically developed a mouse model which recapitulates key characteristics of temporal lobe epilepsy in humans.
“In this model, we were able to demonstrate that during the development of epilepsy, the coupling between the astrocytes is lost very early, and changes in the neurons are observed only later on,” reports Prof. Steinhäuser.
The researchers suspect that uncoupling of astrocytes is mediated by inflammation. The causes are likely so-called cytokines which are released in the brain by activated microglial cells or astrocytes.
“We were able to demonstrate that uncoupling of astrocytes – at least in the early stage of epilepsy – can be reversed,” says Prof. Steinhäuser.
The scientists now hope that their results from basic research will enable the development of new therapies to treat temporal lobe epilepsy.
P. Bedner, A. Dupper, K. Huttmann, J. Muller, M. K. Herde, P. Dublin, T. Deshpande, J. Schramm, U. Haussler, C. A. Haas, C. Henneberger, M. Theis, C. Steinhauser. Astrocyte uncoupling as a cause of human temporal lobe epilepsy. Brain, 2015; DOI: 10.1093/brain/awv067
Photo: obtained by filling an astrocyte with a marker (biocytin, red) in a section of the brain. When coupling is intact, this molecule diffuses into neighboring astrocytes and an entire functional network thus becomes visible. Credit: Institute of Cellular Neurosciences/University of Bonn