Synergistic hyperactivation of both mTORC1 and mTORC2 underlies the neural abnormalities of PTEN-deficient human neurons and cortical organoids

Authors: Navroop K. Dhaliwal, Octavia Yifang Weng, Xiaoxue Dong, Afrin Bhattacharya, Mai Ahmed, Haruka Nishimura, Wendy W.Y. Choi, Aditi Aggarwal, Bryan W. Luikart, Qiang Shu, Xuekun Li, Michael D. Wilson, Jason Moffat, Lu-Yang Wang, Julien Muffat, and Yun Li 

Cell Reports, 28 May 2024

Axion’s noninvasive, label-free Maestro MEA to explore neural activity in PTEN-mutant neurons in vitro.  

Research has shown that loss of PTEN alters human neural development and function, but the underlying mechanisms are not fully understood. In this study, scientists investigate how PTEN loss-of-function mutations and downstream mTOR hyperactivation disrupts neural development and contributes to neurodevelopmental disorders such as autism spectrum disorder and epilepsy. Using Axion’s hands-free Maestro multielectrode array (MEA) platform, the team characterized PTEN-mutant neurons and mechanistic contributions of mTOR hyperactivation in vitro. MEA results demonstrated that PTEN-mutant neurons exhibited hyperactivity, which was rescued by mTOR inhibition via rapamycin treatment or genetic inhibition of mTOR-associated genes. Taken together with other results, the authors’ findings “have potential mechanistic implications on a wide spectrum of neurodevelopmental disorders that display mTOR hyperactivation,” including focal cortical dysplasia, fragile X syndrome, and others,  and conclude that “ future investigations are required to reveal the contribution of mTORC1 and mTORC2 to the etiology of these diverse neurodevelopmental disorders in order to provide new mechanistic insights and inform therapeutic strategies.”