Loss of circadian rhythmicity in knockout zebrafish larvae.

Brain-derived neurotrophic factor (BDNF) plays a pivotal role in neuronal growth and differentiation, neuronal plasticity, learning, and memory. Using CRISPR/Cas9 technology, we generated a vital Bdnf null mutant line in zebrafish and carried out its molecular and behavioral characterization. Although no defects are evident on a morphological inspection, 66% of coding genes and 37% of microRNAs turned out to be differentially expressed in compared with wild type sibling embryos. We deeply investigated the circadian clock pathway and confirmed changes in the rhythmic expression of clock (, and ) and clock-controlled () genes. The modulatory role of Bdnf on the zebrafish circadian clock was then validated by behavioral tests highlighting the absence of circadian activity rhythms in larvae. The circadian behavior was partially rescued by pharmacological treatment. The zebrafish line presented here is the first valuable and stable vertebrate model for the study of BDNF-related neurodevelopmental diseases.