Treating Hyperexcitability in Human Cerebral Organoids Resulting from Oxygen-Glucose Deprivation

Alexandra C Santos; George Nader; Dana El Soufi El Sabbagh; Karolina Urban; Liliana Attisano; Peter L Carlen

doi:10.3390/cells12151949

Treating Hyperexcitability in Human Cerebral Organoids Resulting from Oxygen-Glucose Deprivation

Cells. 2023 Jul 27;12(15):1949. doi: 10.3390/cells12151949.

Authors

Alexandra C Santos^{1

2}, George Nader¹, Dana El Soufi El Sabbagh^{1

3}, Karolina Urban⁴, Liliana Attisano^{5

6}, Peter L Carlen^{1

2}

Affiliations

¹ Krembil Research Institute, University Health Network, Toronto, ON M5S 0T8, Canada.
² Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 1A1, Canada.
³ Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A1, Canada.
⁴ Avicanna Inc., Toronto, ON M5G 1V2, Canada.
⁵ Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A1, Canada.
⁶ Donnelly Centre, University of Toronto, Toronto, ON M5S 1A1, Canada.

Abstract

Human cerebral organoids resemble the 3D complexity of the human brain and have the potential to augment current drug development pipelines for neurological disease. Epilepsy is a complex neurological condition characterized by recurrent seizures. A third of people with epilepsy do not respond to currently available pharmaceutical drugs, and there is not one drug that treats all subtypes; thus, better models of epilepsy are needed for drug development. Cerebral organoids may be used to address this unmet need. In the present work, human cerebral organoids are used along with electrophysiological methods to explore oxygen-glucose deprivation as a hyperexcitability agent. This activity is investigated in its response to current antiseizure drugs. Furthermore, the mechanism of action of the drug candidates is probed with qPCR and immunofluorescence. The findings demonstrate OGD-induced hyperexcitable changes in the cerebral organoid tissue, which is treated with cannabidiol and bumetanide. There is evidence for NKCC1 and KCC2 gene expression, as well as other genes and proteins involved in the complex development of GABAergic signaling. This study supports the use of organoids as a platform for modelling cerebral cortical hyperexcitability that could be extended to modelling epilepsy and used for drug discovery.

Keywords: GABA; brain; electrophysiology; epilepsy; organoids.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Brain / metabolism
Epilepsy* / drug therapy
Epilepsy* / metabolism
Glucose* / metabolism
Humans
Organoids / metabolism
Solute Carrier Family 12, Member 2 / metabolism

Substances

Solute Carrier Family 12, Member 2
Glucose

Grants and funding

This research is funded by Epilepsy Canada to P.C., NSERC-CGS-M to A.C.S., Mitacs/Avicanna Inc. to A.C.S., Medicine by Design/CFREF grants to P.C. and L.A, Ontario Centres of Excellence/Avicanna Inc. to P.C., and a Brain Canada Platform grant to L.A.