Inhibition of neurotransmitter release by a nonphysiological target requires protein synthesis and PKA/MAP kinases in Helix neurons in culture

During development of neuronal circuits, the contact of axonal growth coneswith their physiological targets leads to an upregulation of neurotransmittersecretion. On the other hand, in previous experiments, we have found thatgrowth cones of the Helix serotonergic neuron C1 downregulateneurotransmitter release upon contact with a nonphysiologicaltarget suchas the neuron C3. This wrong targetmediatedinhibition is reversed by a fewminutes contact with the physiological target B2, which induces a promptenhancement of neurotransmitter release and a subsequent increase in thenumber of presynaptic varicosities.In these experiments, we show that the contact with a nonphysiologicaltarget inhibits neurotransmitter release from developing presynapticterminals by means of an active mechanism requiring ongoing proteinsynthesis and leading to the inhibition of the same protein kinases that areactivated following contact with a physiological target neuron. The reversalof the inhibitory effect of the nonphysiologicaltarget by blockade of proteinsynthesis is prevented by cAMP/PKA or MAPK/Erk inhibitors, whereas thefacilitatory effect of the cAMP/PKA activation is not affected by MAPK/Erkinhibitors.The data indicate that the inhibitory effect of the nonphysiologicaltarget onneurotransmitter release is an active process that requires protein synthesisand the downstream sequential activation of the MAPK/Erk and cAMPPKApathways. These mechanisms could play an important role in the formationof neuronal circuits during development by modulating the neurotransmitterrelease capability in a targetdependentmanner.