Art - Poo (D)

nature neuroscience • volume 2 no 4 • april 1999 Activity-dependent synaptic modifications are crucial to the normal development and function of the nervous system, but the basic underlying mechanisms are not fully understood. Recently, it has been proposed that activity-dependent synaptic plasticity may involve a family of secreted proteins known as neurotrophins1–5. Neurotrophins were initially identified based on their ability to promote neuronal survival and morphological differentiation6. Several lines of evidence have suggested a role for neurotrophins in synaptic plasticity. First, the expression of many neurotrophins is upregulated by electrical activity7–9, and the secretion of neurotrophins is triggered by depolarization or synaptic activity10–12. Second, acute application of neurotrophins results in potentiation of synaptic transmission at peripheral13,14 and central synapses15–18 as well as morphological changes in developing nerve processes19–22. Third, manipulations of the level of neurotrophins influence activity-dependent segregation of thalamocortical afferents in the developing visual system23,24 and innervation of sympathetic ganglia25. Fourth, the neurotrophin BDNF is required for normal induction of long-term potentiation (LTP) in the CA1 region of the hippocampus26–29. How might neurotrophins influence activity-dependent synaptic plasticity? Activity can induce synthesis and secretion of neurotrophins, which in turn modulate synaptic structure or efficacy of synaptic transmission. To account for activity-dependent synaptic modifications, however, it would be important to restrict the synaptic action of secreted neurotrophins to those inputs that are active at the time when neurotrophins are released. Restriction may be accomplished by a localized secretion of neurotrophin at the site of active synapses and a limited spread of secreted neurotrophins30,31. Alternatively, it has been suggested that active presynaptic terminals may be more susceptible to the modulatory actions of secreted neurotrophins29,32,33. Such an effect of activity on neurons’ synaptic responsiveness to neurotrophins has not been directly demonstrated. In the present study, we addressed this issue by studying the effect of activity on the action of neurotrophins at Xenopus neuromuscular synapses in culture. Our findings indicate that presynaptic depolarization in the presence of BDNF greatly facilitates the potentiation of transmitter release induced by BDNF. These results provide direct evidence for the activity-dependent synaptic action of neurotrophins, a mechanism that may be crucial in conferring an advantage to active inputs during refinement of developing nerve connections.