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

作者：Costa Veronica^*; Aigner Stefan; Vukcevic Mirko; Sauter Evelyn; Behr Katharina; Ebeling Martin; Dunkley Tom; Friedlein Arno; Zoffmann Sannah; Meyer Claas A; Knoflach Frederic; Lugert Sebastian; Patsch Christoph; Fjeldskaar Fatiha; Chicha Gaudimier Laurie; Kiialainen Anna; Piraino Paolo; Bedoucha Marc; Graf Martin; Jes**erger Sebastian; Ghosh Anirvan; Bischofberger Josef; Jagasia Ravi

来源：Cell Reports, 2016, 15(1): 86-95.

DOI：10.1016/j.celrep.2016.02.090

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.

• 出版日期2016-4-5