Unique and overlapping behavioral effects of isoform-specific NRXN1 deletions

Mutations in the human neurexin 1 (NRXN1) gene are associated with neurodevelopmental disorders including autism and schizophrenia. Vertebrate NRXN1 produces three major NRXN1 isoforms, referred to as α, β and γ. Human genetic data suggest that deletions located at the 5' region of the gene disrupting the α isoform associate mostly with clinical behavioral deficits. Yet, 3' deletions that disrupt multiple isoforms have also been identified in clinical cases. Whether deletions that selectively affect specific NRXN1 isoforms result in specific behavioral deficits remains unclear. Here, combining larval sensorimotor assays with a custom hands-free social preference assay developed for juvenile zebrafish, we show that zebrafish harboring Nrxn1 deletions that differentially encompass α, β and/or γ isoforms display both unique and overlapping locomotion, sensorimotor behavior, and social behavior deficits. Combined, our results strongly support a model by which domain-selective nrxn1 deletions predict behavioral phenotypes. Moreover, our results demonstrate compelling relationships between genotype and resulting behavioral phenotypes, providing functional insights into the complexity of NRXN1-associated neuropsychiatric behaviors.