Trinity group describe the first model of mitochondrial epilepsy

A Trinity College research group have made a revelation in epilepsy research by becoming the first group to describe a model of mitochondrial epilepsy. This raises the possibility of more effective therapies being developed in the future. The paper which outlines these findings was published in BRAIN, a peer reviewed journal of neurology.

Mitochondrial related diseases are extremely common affecting one in 9000 births in Ireland with serious conditions. Over one quarter of people that are affected by mitochondrial related diseases also have epilepsy. People in this situation often have more severe forms of epilepsy and are more resistant toward antiepileptic drugs.

Until these recent findings there have been no biological models available to aid researchers in understanding the mechanics of the condition.

These new models have allowed the research group from Trinity College Dublin to explain the role of astrocytes in seizure generation. Until this point, the star shaped cells found in the brain and spinal cord, have generally accepted to be “supporting-cells” that plated a passive role in the brain. However this new research produced in Trinity College Dublin shows that they actually play an integral role in seizure generation and mitochondrial epilepsy.

The team were able to recreate a brain slice model by the application of an astrocytic-specific aconitase inhibitor, fluorocitrate, concomitant with mitochondrial respiratory inhibitors, rotenone and potassium cyanide. The model was flexible and exhibited both face and predictive validity.

The group then utilised the model so they could examine how astrocytes and seizure generation are linked. They also managed to demonstrate the involvement of the GABA-glutamate-glutamine cycle. This regulates how chemical transmitters are released from neurons and then taken up by the supporting cells; the astrocytes.

It was interesting to note that glutamine appeared as an intermediary molecule between the neuronal and astrocytic compartment in the regulation of GABAergic inhibitory tone.

The research team also found that a deficiency in glutamine synthetase is an important part of the pathogenic process for seizure generation in both the brain slice model and the human neuropathological study.

Explaining the importance of the research, Ellen Mayston Bates Professor of Neurophysiology of Epilepsy at Trinity, Mark Cunningham said: "We believe this is important and novel research as it produces, for the first time, a model of mitochondrial epilepsy which captures features observed in patients. The model provides mechanistic insights, demonstrating the role of astrocytes in this pathological activity."

Looking ahead and considering how this research translates to treat those with mitochondrial epilepsy, Professor Cunningham said: "We believe this work is important in providing new avenues with regard to producing better therapies for this condition. Future work will develop the model so that it can be used to stratify novel anti-seizure drugs in a tailored manner for patients diagnosed with mitochondrial disorders and who phenotypically exhibit epilepsy."