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

Lookup NU author(s): Dr Nichola Lax, Shuna Whyte, Dr Alistair Jenkins, Emeritus Professor Doug Turnbull, Mark Cunningham

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Abstract

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.

Publication metadata

Author(s): Chan F, Lax NZ, Voss CM, Aldana BI, Whyte S, Jenkins A, Nicholson C, Nichols S, Tilley E, Powell Z, Waagepetersen HS, Davies CH, Turnbull DM, Cunningham MO

Publication type: Article

Publication status: Published

Journal: Brain

Year: 2019

Volume: 142

Issue: 2

Pages: 391-411

Print publication date: 01/02/2019

Online publication date: 24/01/2019

Acceptance date: 29/10/2018

ISSN (electronic): 0006-8950

Publisher: Oxford University Press

URL: https://doi.org/10.1093/brain/awy320

DOI: 10.1093/brain/awy320

PubMed id: 30689758

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