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First model of mitochondrial epilepsy developed


Researchers from Trinity College Dublin publishing in BRAIN describes for the first time a model of mitochondrial epilepsy. Mitochondrial disease is one of the most common forms of genetic diseases, affecting one in 9,000 births in Ireland with debilitating consequences. A quarter of patients with mitochondrial disease have epilepsy which is often severe and resistant towards conventional antiepileptic drugs.

Currently no animal models are available to provide a mechanistic understanding of the condition. The current study has thrown light at the important role that astrocytes play in driving seizure generation in mitochondrial epilepsy. They recreated 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 model was then used 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.

They 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. 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."

Story Source: Trinity College Dublin

Journal Reference:

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, Mark O Cunningham. The role of astrocytes in seizure generation: insights from a novel in vitro seizure model based on mitochondrial dysfunction. Brain, 2019; 142 (2): 391 DOI: 10.1093/brain/awy320

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