Synapsin III Controls Early Phases of Dopaminergic Neurons Development in Fishes and Mammals by Acting Upstream of BDNF and Cdk5 Signaling

Polymorphisms in the Synapsin III (Syn III) gene can associate with attention deficits and hyperactivity disorder (ADHD), a neurodevelopmental disorder characterized by alterations in the mesocorticolimbic and nigrostriatal dopaminergic pathways. In spite of evidence supporting that Syn III controls the development of cortical and hippocampal short-projecting neurons, whether it plays a similar role in midbrain dopaminergic neurons (mDN), owning extensively arborized long-distance multisynaptic axonal projections, was unexplored.Our studies on mDN development in zebrafish embryos exposed to Syn III gene knock-down (KD), Syn III knock-out (ko) mice and Syn III-deleted human induced pluripotent stem cells (iPSCs)-derived neurons disclose that Syn III governs early mDN developmental stages in fishes and mammals. Differently to what observed in cortical and hippocampal neurons, this occurs through the upstream control of brain derived neurotrophic factor (BDNF)-mediated and cAMP-dependent protein kinase 5 (Cdk5)-stimulated dendrite development. These findings have significant implications for deciphering the basis of ADHD.