Abstract
Neuronal communication starts before the establishment of the synapses with forms of neuronal excitability occurring during the embryonic period, we 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 as a proxy for ENE in zebrafish to assess the efficacy of transient pharmacological treatments applied by balneation during the embryonic period to modulate ENE. We also report lasting effects of 24h treatments, performed at the end of the embryonic development, on morphology and behavior of larval zebrafish.
The post-mitotic differentiation of the dopaminergic phenotype is modulated by ENE in the forebrain. The plasticity of the dopaminergic specification occurs within a stable population of vMAT2 immuno-reactive cells, hence identifying an unanticipated biological marker for this reserve pool.
We also report an effect of ENE on locomotion several days after the end of the treatments. In particular, the increase of ENE from 2 to 3 dpf promoted an hyperlocomotion in 6dpf zebrafish larvæ which is an endophenotype for Attention Deficit with Hyperactivity Disorders and schizophrenia in zebrafish. These results provide a convenient framework to identify environmental factors that could regulate ENE and to study further the molecular mechanisms linking ENE to the neurotransmitters specification, with clinical relevance for the pathogenesis of neurodevelopmental disorders.
Significance Statement
- Spontaneous 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Conflict of interest statement: The authors declare no competing financial interests.
Funding sources: This work was funded by the French National Research Agency (ANR project “PallEnody”) and the Fondation pour la Médicale Recherche, FRM (“team FRM”).