Abnormal brain development of monoamine oxidase mutant zebrafish and impaired social interaction of heterozygous fish

Abstract

Monoamine oxidase (MAO) deficiency and imbalanced levels of brain monoamines have been associated with developmental delay, neuropsychiatric disorders and aggressive behavior. Animal models are valuable tools to gain mechanistic insight into outcomes associated with MAO deficiency. Here we report a novel genetic model to study the effects of mao-loss-of-function in zebrafish. Quantitative PCR, in situ hybridization and immunocytochemistry were used to study neurotransmitter systems, and expression of relevant genes for brain development in zebrafish mao mutants. Larval and adult fish behavior was evaluated through different tests. A stronger serotonin immunoreactivity was detected in both mao+/- and mao−/- larvae when compared with mao+/+ siblings. Mao−/- larvae were hypoactive, presented decreased reactions to visual and acoustic stimuli. They also had impaired histaminergic and dopaminergic systems, abnormal expression of developmental markers, and they died within 20 days post-fertilization. Mao+/- fish were viable, grew until adulthood and demonstrated anxiety-like behavior and impaired social interactions when compared with adult mao+/+ siblings. Our results indicate that mao−/- and mao+/- mutants could be promising tools to study the roles of MAO in brain development and behavior.

AnAstyanax mexicanus maoknockout line uncovers the developmental roles of monoamine homeostasis in fish brain

“…We also performed locomotion assays in 2 months old juveniles, and observed hyperactivity of the heterozygotes compared to the WT. These results are different from those obtained in adult zebrafish mao knockouts, where no difference was found (Baronio et al, 2022).…”

“…(see Baronio et al, 2022), those we discovered on the fine regulation of serotonin content in different brain neuronal clusters on one hand, and on the control of brain progenitor proliferation on the other hand, were unexpected and open novel research opportunities.…”

“…Serotonin and MAO have demonstrated roles in the control of locomotor activity in 6 dpf zebrafish larvae (Baronio et al, 2022;Sallinen et al, 2009). As 5-HT content in neurons followed important Moreover, before this stage the larvae had a rather limited locomotion, independently of their genotype.…”

“…A zebrafish knockout line for mao was recently generated. The mao knockout larvae are hypoactive at 6 days post‐fertilization (dpf) and they have stronger serotonin immunoreactivity in their brains at 10 dpf (Baronio et al, 2022). In A. mexicanus on the other hand, the mao P106L mutation, which affects brain monoamines levels (Pierre et al, 2023), has a tendency to decrease basal anxiety in a familiar environment, but strongly increases the amplitude of stress response after environmental change.…”

First person – Diego Baronio

“… ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Diego Baronio is first author on ‘ Abnormal brain development of monoamine oxidase mutant zebrafish and impaired social interaction of heterozygous fish ’, published in DMM. Diego is a PhD student in the lab of Pertti Panula at the University of Helsinki, Helsinki, Finland, investigating mechanisms involved in the pathophysiology of neurodevelopmental disorders.…”