Loss of circadian rhythmicity in bdnf 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 car- ried out its molecular and behavioral characterization. Although no defects are evident on a morphological inspection, 66% of coding genes and 37% of micro- RNAs turned out to be differentially expressed in bdnf / compared with wild type sibling embryos. We deeply investigated the circadian clock pathway and confirmed changes in the rhythmic expression of clock (arntl1a, clock1a and clock2) and clock-controlled (aanat2) 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 bdnf / larvae. The circadian behavior was partially rescued by pharmacological treatment. The bdnf / zebrafish line presented here is the first valuable and stable vertebrate model for the study of BDNF-related neurodevelopmental diseases.