Cross-platform validation of neurotransmitter release impairments in schizophrenia patient-derived NRXN1-mutant neurons

Abstract

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.