Plasticity of dopaminergic phenotype and locomotion in larval zebrafish induced by brain excitability changes during the embryonic period

During the embryonic period, neuronal communication starts before the establishment of the synapses with alternative forms of neuronal excitability, called here Embryonic Neural Excitability (ENE). ENE has been shown to modulate the unfolding of development transcriptional programs, but the global consequences for developing organisms are not all understood. Here we monitored calcium transients in the telencephalon of zebrafish embryos as a proxy for ENE to assess the efficacy of transient pharmacological treatments to either increase or decrease ENE. Increasing or decreasing ENE at the end of the embryonic period promoted an increase or a decrease in the numbers of dopamine (DA) neurons, respectively. This plasticity of dopaminergic specification occurs in the subpallium of zebrafish larvæ at 6 dpf, within a relatively stable population of vMAT2-positive cells. Non-dopaminergic vMAT2-positive cells hence constitute an unanticipated biological marker for a reserve pool of DA neurons that can be recruited by ENE.Modulating ENE also affected larval locomotion several days after the end of the treatments. In particular, the increase of ENE from 2 to 3 dpf promoted hyperlocomotion of larvæ at 6 dpf, reminiscent of zebrafish endophenotypes reported for Attention Deficit with Hyperactivity Disorders. These results provide a convenient framework for identifying environmental factors that could disturb ENE as well as to study the molecular mechanisms linking ENE to neurotransmitter specification.Significance Statement- Spontaneous calcium transients, used as a proxy for Embryonic Neural Excitability (ENE), are detected in the forebrain of embryonic zebrafish.- Short-term pharmacological treatments by bath application could increase or decrease ENE.- The post-mitotic differentiation of the dopaminergic phenotype is modulated by ENE in the zebrafish forebrain.- The plasticity of the dopaminergic specification occurs within a reserve pool of vMAT2-positive cells.- Transient increase of ENE at the end of the embryonic period induces hyperlocomotion, a phenotype associated with ADHD in this model.- Our results provide a convenient framework to study the molecular mechanisms linking ENE to neurotransmitter specification.