SummaryMAPK/Erk is a protein kinase activated by neurotrophic factors involved in synapse formation and plasticity, which acts at both the nuclear and cytoplasmic level. Synapsin proteins are synaptic-vesicle-associated proteins that are well known to be MAPK/Erk substrates at phylogenetically conserved sites. However, the physiological role of MAPK/Erk-dependent synapsin phosphorylation in regulating synaptic formation and function is poorly understood. Here, we examined whether synapsin acts as a physiological effector of MAPK/Erk in synaptogenesis and plasticity. To this aim, we developed an in vitro model of soma-to-soma paired Helix B2 neurons, that establish bidirectional excitatory synapses. We found that the formation and activity-dependent short-term plasticity of these synapses is dependent on the MAPK/Erk pathway. To address the role of synapsin in this pathway, we generated non-phosphorylatable and pseudo-phosphorylated Helix synapsin mutants at the MAPK/Erk sites. Overexpression experiments revealed that both mutants interfere with presynaptic differentiation, synapsin clustering, and severely impair post-tetanic potentiation, a form of short-term homosynaptic plasticity. Our findings show that MAPK/Erk-dependent synapsin phosphorylation has a dual role both in the establishment of functional synaptic connections and their short-term plasticity, indicating that some of the multiple extranuclear functions of MAPK/Erk in neurons can be mediated by the same multifunctional presynaptic target.

By using antibodies against mouse F3/contactin, we found immunologically related glycoproteins expressed in the nervous tissue of the snail Helix pomatia. Helix contactin-related proteins (HCRPs) include different molecules ranging in size from 90 to 240 kD. Clones isolated from a cDNA expression library allowed us to demonstrate that these proteins are translated from a unique 6.3-kb mRNA, suggesting that their heterogeneity depends on posttranslational processing. This is supported by the results of endoglycosidase F treatment, which indicate that the highmolecular-weight components are glycosylation variants of the 90-kD chain. In vivo and in cultures, HCRPs antibodies label neuronal soma and neurite extensions, giving the appearance of both cytoplasmic and cell surface immunostaining. On the other hand, no expression is found on nonneural tissues. Functionally, HCRPs are involved in neurite growth control and appear to modulate neurotransmitter release, as indicated by the inhibiting effects of specific antibodies on both functions. These data allow the definition of HCRPs glycoproteins as growth-promoting molecules, suggesting that they play a role in neurite development and presynaptic terminal maturation in the invertebrate nervous system. Keywords axonal glycoproteins; neurite growth; neurotransmitter release; F3/contactinIn vertebrates, axonal growth and pathfinding control depend on mechanisms involving a large set of neuronal surface glycoproteins, which belong to distinct families (Dickson, 2002;De Castro, 2003;Wen and Zheng 2006;Maness and Schachner, 2007). In particular, molecules built by the association of immunoglobulin type C2 and fibronectin type III (FNIII) domains play a relevant role in basic events of neuronal differentiation as axonal growth, fasciculation, and pathfinding (Brummendorf and Lemmon, 2001), a role also played by several extracellular matrix components (Galtrey and Fawcett, 2007). Depending on the mechanism of membrane association, axonal surface glycoproteins may be classified

TitleSynapsin knock-down is associated with decreased neurite outgrowth, functional synaptogenesis impairment and fast high frequency neurotransmitter release. Authors

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In mammalian brain, the cellular and molecular events occurring in both synapse formation and plasticity are difficult to study due to the large number of factors involved in these processes and because the contribution of each component is not well defined. Invertebrates, such as Drosophila, Aplysia, Helix, Lymnaea, and Helisoma, have proven to be useful models for studying synaptic assembly and elementary forms of learning. Simple nervous system, cellular accessibility, and genetic simplicity are some examples of the invertebrate advantages that allowed to improve our knowledge about evolutionary neuronal conserved mechanisms. In this paper, we present an overview of progresses that elucidates cellular and molecular mechanisms underlying synaptogenesis and synapse plasticity in invertebrate varicosities and their validation in vertebrates. In particular, the role of invertebrate synapsin in the formation of presynaptic terminals and the cell-to-cell interactions that induce specific structural and functional changes in their respective targets will be analyzed.