Cross-platform validation of neurotransmitter release impairments in schizophrenia patient-derived <i>NRXN1</i> -mutant neurons
ChangHui Pak, Tamás Dankó, Vincent R. Mirabella, Jinzhao Wang, Yingfei Liu, Madhuri Vangipuram, Sarah D. Grieder, Xianglong Zhang, Thomas Ward, Yu‐Wen Alvin Huang, Kang Jin, Phillip J. Dexheimer, Eric E. Bardes, Alexis Mitelpunkt, Junyi Ma, Michael J. McLachlan, Jennifer C. Moore, Pingping Qu, Carolin Purmann, Jeffrey L. Dage, Bradley Jay Swanson, Alexander E. Urban, Bruce J. Aronow, Zhiping P. Pang, Douglas F. Levinson, Marius Wernig, Thomas C. Südhof
Abstract
Significance Heterozygous NRXN1 deletions predispose to schizophrenia and other neurodevelopmental disorders. Engineered heterozygous NRXN1 deletions impair neurotransmitter release in human neurons, suggesting a synaptic pathophysiological mechanism. In a multicenter effort to test the generality and robustness of this pivotal observation, we used, at two laboratories, independent analyses of patient-derived and newly engineered human neurons with heterozygous NRXN1 deletions. Schizophrenia patient-derived neurons with NRXN1 deletions exhibited the same major decrease in neurotransmitter release and an increase in CASK protein as engineered human neurons with NRXN1 deletions. Strikingly, engineered mouse Nrxn1 -deficient neurons derived by the same method displayed no such phenotype, suggesting a human-specific role for NRXN1 . Thus, heterozygous NRXN1 deletions robustly impair synaptic function in human neurons, enabling future drug discovery efforts.