SYNAPTIC MODULATION BY NEUROTROPHIC FACTORS - DIFFERENTIAL AND SYNERGISTIC EFFECTS OF BRAIN-DERIVED NEUROTROPHIC FACTOR AND CILIARY NEUROTROPHIC FACTOR

Extracellular application of brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) to developing neuromuscular jun ctions in Xenopus nerve-muscle cultures resulted in an increase in the frequency of spontaneous synaptic currents (SSCs) and in the amplitud e of nerve-evoked synaptic currents. Analyses of the amplitude and tim e course of the SSCs suggest that these effects are attributable to el evation of presynaptic transmitter release. The actions of these two f actors on the transmitter secretion process, however, are distinctly d ifferent. Fura-2 Ca2+ imaging showed that an increase in presynaptic c ytosolic Ca2+ ([Ca2+](i)) accompanied the synaptic potentiation by BDN F, whereas no change in [Ca2+](i) was observed during synaptic potenti ation by CNTF, Removing external Ca2+ also abolished the potentiating effect of BDNF but did not influence the CNTF effect, Moreover, the tw o factors exerted different effects on the short-term synaptic plastic ity. Paired-pulse facilitation normally found at these synapses was re duced by BDNF but unaffected by CNTF; CNTF, but not BDNF, reduced the extent of synaptic depression during high-frequency tetanic stimulatio n. Finally, the potentiation effect of BDNF and CNTF on spontaneous tr ansmitter release was additive when both factors were applied together to the synapse at saturating concentrations (100 ng/ml) and was highl y synergistic when low doses (1 and 10 ng/ml) of both factors were use d, These results suggest that because of their differential effects on the secretory machinery, BDNF and CNTF may act cooperatively in modul ating the development and functioning of synapses.