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

Abstract

During the embryonic period, neuronal communication starts before the establishment of the synapses with alternative forms of neuronal excitability, called here Embryonic Neuronal Excitability (ENE). ENE has been shown to modulate the unfolding of development transcriptional programs but the global consequences for the developing organisms are not all understood. Here we monitored calcium transients in 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 for 24 hours at 2 days post fertilization (dpf), at the end of the embryonic period, promoted respectively an increase or a decrease in the numbers of dopamine (DA) neurons in the telencephalon and in the olfactory bulb of zebrafish larvae at 6 dpf. This plasticity of dopaminergic specification occurs within a stable population of vMAT2-positive cells, hence identifying an unanticipated biological marker for this reserve pool of of DA neurons that can be recruited by increasing 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 larvae at 6 dpf, reminiscent of endophenotypes reported for Attention Deficit with Hyperactivity Disorders and schizophrenia in zebrafish. These results provide a convenient framework to identify environmental factors that could disturb ENE as well as to study the molecular mechanisms linking ENE to neurotransmitter specification, with relevance to the pathogenesis of neurodevelopmental disorders. Significance Statement- Spontaneous calcium transients, used as a proxy for Embryonic Neuronal 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 and schizophrenia in this model. - Our results open clinically relevant perspectives to study the pathogenesis of neurodevelopmental disorders in zebrafish.