Neuron-glia interactions increase neuronal phenotypes in tuberous sclerosis complex patient iPSC-derived models

Nadadhur, Aishwarya G., Alsaqati, Mouhamed, Gasparotto, Lisa, Cornelissen-Steijger, Paulien, van Hugte, Eline, Dooves, Stephanie, Harwood, Adrian J. ORCID: https://orcid.org/0000-0003-3124-5169 and Heine, Vivi M. 2019. Neuron-glia interactions increase neuronal phenotypes in tuberous sclerosis complex patient iPSC-derived models. Stem Cell Reports 12 (1) , pp. 42-56. 10.1016/j.stemcr.2018.11.019

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Abstract

Tuberous sclerosis complex (TSC) is a rare neurodevelopmental disorder resulting from autosomal dominant mutations in the TSC1 or TSC2 genes, leading to a hyperactivated mammalian target of rapamycin (mTOR) pathway, and gray and white matter defects in the brain. To study the involvement of neuron-glia interactions in TSC phenotypes, we generated TSC patient induced pluripotent stem cell (iPSC)-derived cortical neuronal and oligodendrocyte (OL) cultures. TSC neuron mono-cultures showed increased network activity, as measured by calcium transients and action potential firing, and increased dendritic branching. However, in co-cultures with OLs, neuronal defects became more apparent, showing cellular hypertrophy and increased axonal density. In addition, TSC neuron-OL co-cultures showed increased OL cell proliferation and decreased OL maturation. Pharmacological intervention with the mTOR regulator rapamycin suppressed these defects. Our patient iPSC-based model, therefore, shows a complex cellular TSC phenotype arising from the interaction of neuronal and glial cells and provides a platform for TSC disease modeling and drug development.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Biosciences Neuroscience and Mental Health Research Institute (NMHRI)
Additional Information:	This is an open access article under the CC-BY-NC-ND license.
Publisher:	Elsevier
ISSN:	2213-6711
Date of First Compliant Deposit:	4 January 2019
Date of Acceptance:	22 November 2018
Last Modified:	05 May 2023 03:29
URI:	https://orca.cardiff.ac.uk/id/eprint/118113

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