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Diencephalic and Neuropeptidergic Dysfunction in Zebrafish with Autism Risk Mutations

ABSTRACT: Hundreds of human mutations are linked to autism and related disorders, yet the functions of many of these mutated genes during vertebrate neural development are unclear. We generated 28 zebrafish mutants with presumptive protein-truncating mutations or patient-specific missense variants corresponding to autism-risk alleles in 17 human genes. We observed baseline and stimulus-driven behavioral changes at larval stages, as well as social behavior differences in lines tested as juveniles. Imaging whole-brain activity revealed a near identical activity map for mutations in the unrelated genes kmt5b and hdlbpa, defined by increased activity mainly in the diencephalon. Truncating 7 of the 17 risk genes resulted in substantial brain size differences. Using RNA-sequencing, we further defined molecular drivers of the observed phenotypes, identifying targetable disruptions in neuropeptide signaling, neuronal maturation, and cell proliferation. This multi-modal screen has nominated brain regions, cell types, and molecular pathways that may contribute to autism susceptibility.

ORGANISM(S): Danio rerio

PROVIDER: GSE253405 | GEO | 2024/01/18

REPOSITORIES: GEO

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