Neuronal impact of patient-specific aberrant NRXN1α splicing

NRXN1 undergoes extensive alternative splicing, and non-recurrent heterozygous deletions in NRXN1 are strongly associated with neuropsychiatric disorders. We establish that human induced pluripotent stem cell (hiPSC)-derived neurons well represent the diversity of NRXN1 alpha alternative splicing observed in the human brain, cataloguing 123 high-confidence in-frame human NRXN1 alpha isoforms. Patient-derived NRXN1(+/-) hiPSC-neurons show a greater than twofold reduction in half of the wild-type NRXN1 alpha isoforms and express dozens of novel isoforms from the mutant allele. Reduced neuronal activity in patient-derived NRXN1(+/-) hiPSC-neurons is ameliorated by overexpression of individual control isoforms in a genotype-dependent manner, whereas individual mutant isoforms decrease neuronal activity levels in control hiPSC-neurons. In a genotype-dependent manner, the phenotypic impact of patient-specific NRXN1(+/-) mutations can occur through a reduction in wild-type NRXN1 alpha isoform levels as well as the presence of mutant NRXN1 alpha isoforms.