Pro-BDNF-induced synaptic depression and retraction at developing neuromuscular synapses.
Postsynaptic cells generate positive and negative signals that retrogradely modulate presynaptic function. At developing neuromuscular synapses, prolonged stimulation of muscle cells induces sustained synaptic depression. We provide evidence that pro-brain-derived neurotrophic factor (BDNF) is a negative retrograde signal that can be converted into a positive signal by metalloproteases at the synaptic junctions. Application of pro-BDNF induces a dramatic decrease in synaptic efficacy followed by a retraction of presynaptic terminals, and these effects are mediated by presynaptic pan-neurotrophin receptor p75 (p75(NTR)), the pro-BDNF receptor. A brief stimulation of myocytes expressing cleavable or uncleavable pro-BDNF elicits synaptic potentiation or depression, respectively. Extracellular application of metalloprotease inhibitors, which inhibits the cleavage of endogenous pro-BDNF, facilitates the muscle stimulation-induced synaptic depression. Inhibition of presynaptic p75(NTR) or postsynaptic BDNF expression also blocks the activity-dependent synaptic depression and retraction. These results support a model in which postsynaptic secretion of a single molecule, pro-BDNF, may stabilize or eliminate presynaptic terminals depending on its proteolytic conversion at the synapses.
Yang
Feng
F
Section on Neural Development and Plasticity, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Je
Hyun-Soo
HS
Ji
Yuanyuan
Y
Nagappan
Guhan
G
Hempstead
Barbara
B
Lu
Bai
B
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000502:physiology*; D032342:Muscle Cells / Q000502:physiology; D009469:Neuromuscular Junction / Q000254:growth & development*; D017729:Presynaptic Terminals / Q000648:ultrastructure*; D011498:Protein Precursors / Q000378:metabolism / Q000502:physiology*; D020800:Receptor, Nerve Growth Factor / Q000502:physiology*; D013569:Synapses; D009435:Synaptic Transmission; D014981:Xenopus
D019208:Brain-Derived Neurotrophic Factor; D011498:Protein Precursors; D020800:Receptor, Nerve Growth Factor; C426674:brain-derived neurotrophic factor precursor