Researchers Describe First Model of Mitochondrial Epilepsy

Summary: Researchers have developed a new model of mitochondrial epilepsy which captures specific features observed in patients. The new model may help provide better therapies and treatments for the condition.

Source: TCD.

Researchers from Trinity College Dublin have become the first to describe a model of mitochondrial epilepsy which raises hope for better therapies for patients with this incapacitating condition. Their paper has been published in BRAIN, the peer-reviewed international journal of neurology.

Mitochondrial disease is one of the most common forms of genetic diseases, affecting one in 9,000 births in Ireland with debilitating consequences. One quarter of patients with mitochondrial disease have epilepsy which is often severe and resistant towards conventional antiepileptic drugs.

Despite the severity of this epilepsy, up to now there have been no animal models available to provide a mechanistic understanding of the condition.

That is set to change though as researchers at Trinity can now explain the important role that astrocytes play in seizure generation. To date, astrocytes, the characteristic star-shaped glial cells found in the brain and spinal cord, have been seen as ‘supporting-cells’, playing a largely passive assisting role in the brain. This research shows however that they actually play a central role in driving seizure generation in mitochondrial epilepsy.

The researchers were able to recreate a novel 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 robust and exhibited both face and predictive validity.

The team then used the model to assess the role that astrocytes play in seizure generation and demonstrated the involvement of the GABA-glutamate-glutamine cycle, which regulates how chemical transmitters are released from neurons and then taken up by the supporting cells; the astrocytes.

Notably, glutamine appears to be an important intermediary molecule between the neuronal and astrocytic compartment in the regulation of GABAergic inhibitory tone.

Finally, the team 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.

epilepsy brain

Despite the severity of this epilepsy, up to now there have been no animal models available to provide a mechanistic understanding of the condition. NeuroscienceNews.com image is in the public domain.

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.”

About this neuroscience research article

Funding: Funding provided by Wellcome Trust, Engineering & Physical Sciences Research Council, Medical Research Council, Network of European Neuroscience Schools.

Source: Mark Cunningham – TCD
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “The role of astrocytes in seizure generation: insights from a novel in vitro seizure model based on mitochondrial dysfunction” by Felix Chan, Nichola Z Lax, Caroline Marie Voss, Blanca Irene Aldana, Shuna Whyte, Alistair Jenkins, Claire Nicholson, Sophie Nichols, Elizabeth Tilley, Zoe Powell, Helle S Waagepetersen, Ceri H Davies, Doug M Turnbull, and Mark O Cunningham in Brain. Published January 24 2019.
doi:10.1093/brain/awy320

Cite This NeuroscienceNews.com Article
TCD”Researchers Describe First Model of Mitochondrial Epilepsy.” NeuroscienceNews. NeuroscienceNews, 15 February 2019.
<http://neurosciencenews.com/mitochondrial-epilepsy-10747/>.
TCD(2019, February 15). Researchers Describe First Model of Mitochondrial Epilepsy. NeuroscienceNews. Retrieved February 15, 2019 from http://neurosciencenews.com/mitochondrial-epilepsy-10747/
TCD”Researchers Describe First Model of Mitochondrial Epilepsy.” http://neurosciencenews.com/mitochondrial-epilepsy-10747/ (accessed February 15, 2019).

Abstract

The role of astrocytes in seizure generation: insights from a novel in vitro seizure model based on mitochondrial dysfunction

Approximately one-quarter of patients with mitochondrial disease experience epilepsy. Their epilepsy is often severe and resistant towards conventional antiepileptic drugs. Despite the severity of this epilepsy, there are currently no animal models available to provide a mechanistic understanding of mitochondrial epilepsy. We conducted neuropathological studies on patients with mitochondrial epilepsy and found the involvement of the astrocytic compartment. As a proof of concept, we developed a novel brain slice model of mitochondrial epilepsy by the application of an astrocytic-specific aconitase inhibitor, fluorocitrate, concomitant with mitochondrial respiratory inhibitors, rotenone and potassium cyanide. The model was robust and exhibited both face and predictive validity. We then used the model to assess the role that astrocytes play in seizure generation and demonstrated the involvement of the GABA-glutamate-glutamine cycle. Notably, glutamine appears to be an important intermediary molecule between the neuronal and astrocytic compartment in the regulation of GABAergic inhibitory tone. Finally, we found that a deficiency in glutamine synthetase is an important pathogenic process for seizure generation in both the brain slice model and the human neuropathological study. Our study describes the first model for mitochondrial epilepsy and provides a mechanistic insight into how astrocytes drive seizure generation in mitochondrial epilepsy.

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