MAPK/Erk-dependent phosphorylation of synapsin mediates formation of functional synapses and short-term homosynaptic plasticity.
MAPK/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.
Giachello
Carlo Natale Giuseppe
CN
Department of Neuroscience, Section of Physiology, University of Torino, Torino, Italy. carlo.giachello@unito.it
Fiumara
Ferdinando
F
Giacomini
Caterina
C
Corradi
Anna
A
Milanese
Chiara
C
Ghirardi
Mirella
M
Benfenati
Fabio
F
Montarolo
Pier Giorgio
PG
D000595:Amino Acid Sequence; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D016000:Cluster Analysis; D017124:Conserved Sequence; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006372:Helix, Snails / Q000187:drug effects / Q000201:enzymology*; D017774:Long-Term Potentiation / Q000187:drug effects; D008969:Molecular Sequence Data; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010802:Phylogeny; D017729:Presynaptic Terminals / Q000187:drug effects / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000201:enzymology*; D016704:Synapsins / Q000737:chemistry / Q000378:metabolism*; D013997:Time Factors
D002070:Butadienes; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D016704:Synapsins; C113580:U 0126; D048049:Extracellular Signal-Regulated MAP Kinases