TY - JOUR

T1 - The role of astrocytes in seizure generation

T2 - Insights from a novel in vitro seizure model based on mitochondrial dysfunction

AU - Chan, Felix

AU - Lax, Nichola Z.

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.

PY - 2019/2/1

Y1 - 2019/2/1

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.

KW - astrocytes

KW - GABA-glutamate-glutamine cycle

KW - glutamine synthetase

KW - mitochondrial epilepsy

U2 - 10.1093/brain/awy320

DO - 10.1093/brain/awy320

M3 - Journal article

C2 - 30689758

AN - SCOPUS:85060806232

VL - 142

SP - 391

EP - 411

JO - Brain

JF - Brain

SN - 0006-8950

IS - 2

ER -