title: Pro-BDNF-induced synaptic depression and retraction at developing neuromuscular synapses.
abstract: 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.
authors.affiliation: Section on Neural Development and Plasticity, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Yang
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Je
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Ji
authors.forename: Guhan
authors.initials: G
authors.lastname: Nagappan
authors.forename: Barbara
authors.initials: B
authors.lastname: Hempstead
authors.forename: Bai
authors.initials: B
authors.lastname: Lu
mesh_terms: 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
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D011498:Protein Precursors; D020800:Receptor, Nerve Growth Factor; C426674:brain-derived neurotrophic factor precursor