mTORC1 Inhibition Corrects Neurodevelopmental and Synaptic Alterations in a Human Stem Cell Model of Tuberous Sclerosis

Costa, Veronica and Aigner, Stefan and Vukcevic, Mirko and Sauter, Evelyn and Behr, Katharina and Ebeling, Martin and Dunkley, Tom and Friedlein, Arno and Zoffmann, Sannah and Meyer, Claas A. and Knoflach, Frédéric and Lugert, Sebastian and Patsch, Christoph and Fjeldskaar, Fatiha and Chicha-Gaudimier, Laurie and Kiialainen, Anna and Piraino, Paolo and Bedoucha, Marc and Graf, Martin and Jessberger, Sebastian and Ghosh, Anirvan and Bischofberger, Josef and Jagasia, Ravi. (2016) mTORC1 Inhibition Corrects Neurodevelopmental and Synaptic Alterations in a Human Stem Cell Model of Tuberous Sclerosis. Cell Reports, 15 (1). pp. 86-95.

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Hyperfunction of the mTORC1 pathway has been associated with idiopathic and syndromic forms of autism spectrum disorder (ASD), including tuberous sclerosis, caused by loss of either TSC1 or TSC2. It remains largely unknown how developmental processes and biochemical signaling affected by mTORC1 dysregulation contribute to human neuronal dysfunction. Here, we have characterized multiple stages of neurogenesis and synapse formation in human neurons derived from TSC2-deleted pluripotent stem cells. Homozygous TSC2 deletion causes severe developmental abnormalities that recapitulate pathological hallmarks of cortical malformations in patients. Both TSC2(+/-) and TSC2(-/-) neurons display altered synaptic transmission paralleled by molecular changes in pathways associated with autism, suggesting the convergence of pathological mechanisms in ASD. Pharmacological inhibition of mTORC1 corrects developmental abnormalities and synaptic dysfunction during independent developmental stages. Our results uncouple stage-specific roles of mTORC1 in human neuronal development and contribute to a better understanding of the onset of neuronal pathophysiology in tuberous sclerosis.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Physiology > Cellular Neurophysiology (Bischofberger)
UniBasel Contributors:Bischofberger, Josef
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:2211-1247 (Electronic)
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:19 Jan 2019 18:49
Deposited On:19 Jan 2019 18:49

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