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

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

doi:10.1093/brain/awy320

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

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^*

^*Corresponding author for this work

14 Citations (Scopus)

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.

Original language	English
Journal	Brain
Volume	142
Issue number	2
Pages (from-to)	391-411
Number of pages	21
ISSN	0006-8950
DOIs	https://doi.org/10.1093/brain/awy320
Publication status	Published - 1 Feb 2019

Keywords

astrocytes
GABA-glutamate-glutamine cycle
glutamine synthetase
mitochondrial epilepsy

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Chan, F., Lax, N. Z., Voss, C. M., Aldana, B. I., Whyte, S., Jenkins, A., Nicholson, C., Nichols, S., Tilley, E., Powell, Z., Waagepetersen, H. S., Davies, C. H., Turnbull, D. M., & Cunningham, M. O. (2019). The role of astrocytes in seizure generation: Insights from a novel in vitro seizure model based on mitochondrial dysfunction. Brain, 142(2), 391-411. https://doi.org/10.1093/brain/awy320

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 2019, 'The role of astrocytes in seizure generation: Insights from a novel in vitro seizure model based on mitochondrial dysfunction', Brain, vol. 142, no. 2, pp. 391-411. https://doi.org/10.1093/brain/awy320

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title = "The role of astrocytes in seizure generation: Insights from a novel in vitro seizure model based on mitochondrial dysfunction",

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.",

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author = "Felix Chan and Lax, {Nichola Z.} and Voss, {Caroline Marie} and Aldana, {Blanca Irene} and Shuna Whyte and Alistair Jenkins and Claire Nicholson and Sophie Nichols and Elizabeth Tilley and Zoe Powell and Waagepetersen, {Helle S.} and Davies, {Ceri H.} and Turnbull, {Doug M.} and Cunningham, {Mark O.}",

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AU - Chan, Felix

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AU - Voss, Caroline Marie

AU - Aldana, Blanca Irene

AU - Whyte, Shuna

AU - Jenkins, Alistair

AU - Nicholson, Claire

AU - Nichols, Sophie

AU - Tilley, Elizabeth

AU - Powell, Zoe

AU - Waagepetersen, Helle S.

AU - Davies, Ceri H.

AU - Turnbull, Doug M.

AU - Cunningham, Mark O.

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N2 - 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.

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

Abstract

Keywords

UN SDGs

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