New Lab Model Could Shed Light on Mitochondrial Epilepsy and Therapies

Researchers have created the first laboratory model of epilepsy caused by mitochondrial disorders with the potential to improve scientists’ understanding of how this condition unfolds and to develop therapies to combat it.

Until now, no animal models were available to study this severe form of epilepsy, but this new in vitro model (outside a living organism), made of brain slices maintained in lab chambers, could represent an important advance.

In their study, “The role of astrocytes in seizure generation: insights from a novel in vitro seizure model based on mitochondrial dysfunction,” researchers applied this model to demonstrate the important role played by brain cells called astrocytes in triggering seizures during mitochondrial epilepsy.

Their work was published in the journal Brain.

Nearly one-quarter of patients with mitochondrial disease will experience epilepsy. Most times, this type of epilepsy begins during childhood, typically in the first two years of life. Seizures are often severe and resistant to conventional anti-epileptic treatments.

But until now, researchers scarcely understood why this form of epilepsy arises in some patients, partly because of the lack of animal models.

To overcome this, a team led by scientists from Trinity College Dublin, in Ireland, and Newcastle University, in England, developed a way to re-create mitochondrial epilepsy in the laboratory.

Based on examinations of postmortem brain samples of patients, researchers initially suspected that astrocytes would play an important role in the appearance of epilepsy.

So, to create their model, they treated rat brain slices with an astrocyte-specific inhibitor, called fluorocitrate, together with mitochondrial respiratory chain inhibitors, rotenone and potassium cyanide, to reproduce mitochondrial function defects.

They found that such a combination of medications stimulated the production of epilepsy-like electrical discharges, mimicking what happens during a seizure, and they confirmed that an identical response could be reproduced in live human brain slices.

The team used this model to investigate the role that astrocytes — abundant, supporting cells in the brain and spinal cord, key to the proper functioning of nerve cells — play in seizure generation.

Application of the epilepsy model suggests that a recycling flux of neurotransmitters (nerve cell messengers) vital for brain function, called gamma-aminobutyric acid (GABA)-glutamate-glutamine cycle, underlies the development of seizures.

The cycle involves both nerve cells and astrocytes, and sets the production of two central neurotransmitters — glutamate, an excitatory neurotransmitter, and GABA, an inhibitory neurotransmitter. Glutamine, produced in the astrocytes, is the precursor of these two messengers.

This circuitry regulates how much GABA and glutamate are released from nerve cells and taken up by astrocytes — an important function that can control how much of these neurotransmitters are held back in astrocytes and prevented from triggering nerve impulses, or stored for future release.

According to the results, inhibition of this cycle in astrocytes contributes to seizure generation via the intermediary molecule glutamine.

An important finding supporting the role of astrocyte glutamine was that both brain slices of rat models as well as patients with mitochondrial epilepsy were deficient for glutamine synthetase, the enzyme responsible for the production of glutamine.

“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,” Mark Cunningham, professor at Trinity College and a co-senior author of the study, said in a press release.

Emphasizing how this research could translate to patients, 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 [by observable symptoms] exhibit epilepsy.”