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

Heterozygous deletions constitute the most prevalent currently known single-gene mutation associated with schizophrenia, and additionally predispose to multiple other neurodevelopmental disorders. Engineered heterozygous deletions impaired neurotransmitter release in human neurons, suggesting a synaptic pathophysiological mechanism. Utilizing this observation for drug discovery, however, requires confidence in its robustness and validity. Here, we describe a multicenter effort to test the generality of this pivotal observation, using independent analyses at two laboratories of patient-derived and newly engineered human neurons with heterozygous deletions. Using neurons transdifferentiated from induced pluripotent stem cells that were derived from schizophrenia patients carrying heterozygous deletions, we observed the same synaptic impairment as in engineered -deficient neurons. This impairment manifested as a large decrease in spontaneous synaptic events, in evoked synaptic responses, and in synaptic paired-pulse depression. -deficient mouse neurons generated from embryonic stem cells by the same method as human neurons did not exhibit impaired neurotransmitter release, suggesting a human-specific phenotype. Human deletions produced a reproducible increase in the levels of CASK, an intracellular -binding protein, and were associated with characteristic gene-expression changes. Thus, heterozygous deletions robustly impair synaptic function in human neurons regardless of genetic background, enabling future drug discovery efforts.