Browsing by Subject "Synapse formation"

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    Cross-platform validation of neurotransmitter release impairments in schizophrenia patient-derived NRXN1-mutant neurons
    (National Academy of Sciences, 2021) Pak, ChangHui; Danko, Tamas; Mirabella, Vincent R.; Wang, Jinzhao; Liu, Yingfei; Vangipuram, Madhuri; Grieder, Sarah; Zhang, Xianglong; Ward, Thomas; Huang, Yu-Wen Alvin; Jin, Kang; Dexheimer, Philip; Bardes, Eric; Mitelpunkt, Alexis; Ma, Junyi; McLachlan, Michael; Moore, Jennifer C.; Qu, Pingping; Purmann, Carolin; Dage, Jeffrey L.; Swanson, Bradley J.; Urban, Alexander E.; Aronow, Bruce J.; Pang, Zhiping P.; Levinson, Douglas F.; Wernig, Marius; Südhof, Thomas C.; Neurology, School of Medicine
    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.