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

Abstract

ABSTRACTDuring the embryonic period, neuronal communication starts before the establishment of the synapses with forms of neuronal excitability, called here Embryonic Neuronal Excitability (ENE). ENE has been shown to modulate the correct 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 able to either increase or decrease ENE. Increasing or decreasing ENE for 24 hour at 2 days post fertilization (dpf) promoted respectively an increase or decrease in the post-mitotic differentiation of the dopamine (DA) neurons in the telencephalon and in the olfactory bulb of zebrafish larvæ at 6 dpf. This plasticity of dopaminergic specification occurs within a stable population of vMAT2 immuno-reactive cells, hence identifying an unanticipated biological marker for this pool of reserve cells, that can be recruited through ENE.Modulating ENE also affected locomotion several days after the end of the treatments. In particular, the increase of ENE from 2 to 3 dpf promoted an hyperlocomotion in 6 dpf zebrafish larvæ, 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 the neurotransmitters specification, with clinical relevance for the pathogenesis of neurodevelopmental disorders.Significance StatementSpontaneous calcium spikes, used as a proxy for Embryonic Neuronal Excitability (ENE), are detected in the forebrain of embryonic zebrafish.Transients pharmacological treatments applied by balneation could be used to 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 immuno-reactive cells.Transient increase of ENE at the end of the embryonic period induces a 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.