Modeling Epilepsy Using Human Induced Pluripotent Stem Cells-Derived Neuronal Cultures Carrying Mutations in Ion Channels and the Mechanistic Target of Rapamycin Pathway.

Autor:	Weng OY; Program in Developmental and Stem Cell Biology, Sick Kids Research Institutes, Toronto, ON, Canada.; Program in Neuroscience and Mental Health, Sick Kids Research Institutes, Toronto, ON, Canada.; Department of Physiology, University of Toronto, Toronto, ON, Canada., Li Y; Program in Developmental and Stem Cell Biology, Sick Kids Research Institutes, Toronto, ON, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada., Wang LY; Program in Neuroscience and Mental Health, Sick Kids Research Institutes, Toronto, ON, Canada.; Department of Physiology, University of Toronto, Toronto, ON, Canada.
Jazyk:	angličtina
Zdroj:	Frontiers in molecular neuroscience [Front Mol Neurosci] 2022 Mar 10; Vol. 15, pp. 810081. Date of Electronic Publication: 2022 Mar 10 (Print Publication: 2022).
DOI:	10.3389/fnmol.2022.810081
Abstrakt:	Epilepsy is a neurological disorder that affects over 65 million people globally. It is characterized by periods of seizure activity of the brain as a result of excitation and inhibition (E/I) imbalance, which is regarded as the core underpinning of epileptic activity. Both gain- and loss-of-function (GOF and LOF) mutations of ion channels, synaptic proteins and signaling molecules along the mechanistic target of rapamycin (mTOR) pathway have been linked to this imbalance. The pathogenesis of epilepsy often has its roots in the early stage of brain development. It remains a major challenge to extrapolate the findings from many animal models carrying these GOF or LOF mutations to the understanding of disease mechanisms in the developing human brain. Recent advent of the human pluripotent stem cells (hPSCs) technology opens up a new avenue to recapitulate patient conditions and to identify druggable molecular targets. In the following review, we discuss the progress, challenges and prospects of employing hPSCs-derived neural cultures to study epilepsy. We propose a tentative working model to conceptualize the possible impact of these GOF and LOF mutations in ion channels and mTOR signaling molecules on the morphological and functional remodeling of intrinsic excitability, synaptic transmission and circuits, ultimately E/I imbalance and behavioral phenotypes in epilepsy. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Weng, Li and Wang.)
Databáze:	MEDLINE
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