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The Journal of Neuroscience, May 26, 2004, 24(21):5054-5062; doi:10.1523/JNEUROSCI.5671-03.2004

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Cellular/Molecular
Inhibition of Neurotransmitter Release by a Nonphysiological Target Requires Protein Synthesis and Involves cAMP-Dependent and Mitogen-Activated Protein Kinases

Mirella Ghirardi,¹ Fabio Benfenati,² Silvia Giovedì,² Ferdinando Fiumara,¹ Chiara Milanese,¹ and Pier Giorgio Montarolo¹

¹Department of Neuroscience, University of Torino, 10125 Torino, Italy, and ²Department of Experimental Medicine, University of Genova, 16132 Genova, Italy

During the development of neuronal circuits, axonal growth cones can contact many inappropriate targets before they reach an appropriate postsynaptic partner. Although it is well known that the contact with synaptic partners upregulates the secretory machinery of the presynaptic neuron, little is known about the signaling mechanisms involved in preventing the formation of connections with inappropriate target cells. Here, we show that the contact with a nonphysiological postsynaptic target inhibits neurotransmitter release from axonal terminals of the Helix serotonergic neuron C1 by means of an active mechanism requiring ongoing protein synthesis and leading to the inhibition of cAMP-dependent protein kinase (PKA) and mitogen-activated protein kinase (MAPK)-extracellular signal-related kinase (Erk) pathways. The reversal of the inhibitory effect of the nonphysiological target by blockade of protein synthesis was prevented by cAMP-PKA or MAPK-Erk inhibitors, whereas disinhibition of neurotransmitter release promoted by cAMP-PKA activation was not affected by MAPK-Erk inhibitors. The data indicate that the inhibitory effect of the nonphysiological target on neurotransmitter release is an active process that requires protein synthesis and involves the downregulation of the MAPK-Erk and cAMP-PKA pathways, the same protein kinases that are activated after contact with a physiological target neuron. These mechanisms could play a relevant role in the prevention of synapse formation between inappropriate partners by modulating the neurotransmitter release capability of growing nerve terminals according to the nature of the targets contacted during their development.

Key words: target selection; exocytosis; protein synthesis; protein kinases; invertebrate neurons; Helix

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Received Dec 23, 2003; revised March 25, 2004; accepted April 26, 2004.

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