Effects of phosphorylation and neuronal activity on the control of synapse formation by synapsin I.

"Synapsins (Syns) are synaptic vesicle (SV)-associated proteins that regulate synaptic transmission and neuronal differentiation. At early stages, Syns I and II phosphorylation at Ser9 by PKA and CaMK I\/IV modulates axon elongation and SV-precursor dynamics. We evaluated the requirement of Syn I for synapse formation by siRNA-mediated knockdown as well as by overexpression of either its wild type (WT) form or its phospo-mutants. Syn I knockdown at 14 days in vitro (DIV) caused a decrease in the number of synapses, accompanied by a reduction of SV recycling. While overexpression of WT-Syn I was ineffective, overexpression of its phospho-mutants modulated synapse density with a complex temporal regulation. At early stages of synaptogenesis, phosphomimetic S9E-Syn I significantly increased the number of synapses. Conversely, dephosphomimetic S9A-Syn I decreased synapse number at more advanced stages. Overexpression of either WT-Syn I or its phosphomimetic S9E mutant rescued the decrease in synapse number caused by chronic treatment with tetrodotoxin at early stages, suggesting that Syn I participates in an alternative PKA-dependent mechanism that can compensate for the impairment of the activity-dependent synaptogenic pathway. Altogether these results indicate that Syn I is an important regulator of synapse formation, which adjusts synapse number in response to extracellular signals."