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

Gaia Faustini,Franco Onofri,Federica Bono,Francesca Longhena,Marina Pizzi,Alessandro Barbon,Luca La Via,Sneak Peek Administrator,Cristina Missale,Daniela Zizioli,Alessia Muscò,Arianna Bellucci,Edoardo Parrella,Maurizio Memo,Fabio Benfenati

doi:10.2139/ssrn.3902138

Abstract

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.

Highlights

Synapsin III (Syn III) is a neuronal phosphoprotein belonging to the Synapsins (Syns) family together with synapsin I (Syn I) and synapsin II (Syn II)
To corroborate the specificity of syn3 KD on neuronal development and assess whether the Syn III regions controlling neuronal development are conserved in mammals, we investigated the ability of rat Syn III mRNA to rescue the abnormal neuronal phenotype in the zebrafish Tg(neurod1:enhanced green fluorescent protein (eGFP)) embryos injected with Syn III-MO
We found a significant decrease in the length of the axons innervating the 5th 16th somite in the Tg(neurod1:eGFP) embryos injected with Syn III-MO, when compared to their littermates with standard non-targeting morpholino (ST-MO) inoculations (Fig. 4e,h), that was rescued by the injection of rat Syn III mRNA expression plasmid (Fig. 4e,h)

Summary

Introduction

Synapsin III (Syn III) is a neuronal phosphoprotein belonging to the Synapsins (Syns) family together with synapsin I (Syn I) and synapsin II (Syn II). Syn III is implicated in the development of cortical and hippocampal neurons [1,2,3,4,5] and controls striatal dopaminergic neurotransmission in the adult brain [5,6,7]. ADHD is characterized by an impaired development of dopaminergic neurons, reflected by a marked alteration in brain dopamine (DA) synthesis and dopaminergic dysregulations [14,15,16] This supports that Syn III could be implicated in the development of midbrain dopaminergic neurons (mDN), that differently from cortical and hippocampal cells, are characterized by long-distance, extensively arborized multisynaptic axonal projections, connecting with diverse brain areas [17,18,19,20]. Both the mesocorticolimbic and nigrostriatal pathways exhibit alterations in ADHD patients [15, 16, 22]

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