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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)391-411
Number of pages21
JournalBrain : a journal of neurology
Issue number2
Early online date24 Jan 2019
Publication statusPublished - Feb 2019

Bibliographical note

Funding: The study is primarily funded by the EPSRC IndustrialCASE Award (EP/K50499X/1) studentship. This work was also supported by the following grants:The role of astrocytes in seizure generation BRAIN 2019: 142; 391–411 | 409
Downloaded from by aston university library user on 01 November 2022
Wellcome Centre for Mitochondrial Research (203105/Z/
16/Z), The MRC Centre for Ageing and Vitality (MR/
L016354/1), the UK NIHR Biomedical Research Centre
in Age and Age Related Diseases award to the Newcastle
upon Tyne Hospitals NHS Foundation Trust. We thank the
Network of European Neuroscience Schools (NENS)
Exchange Grant for funding the collaborative work done
with University of Copenhagen.


  • Mitochondrial epilepsy
  • Astrocytes
  • Glutamine synthetase
  • GABA-glutamate-glutamine cycle


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