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Pro-BDNF–induced synaptic depression and retraction at developing neuromuscular synapses

¹ Section on Neural Development and Plasticity, National Institute of Child Health and Human Development and ² Genes, Cognition, and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892
³ Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College of Cornell University, New York, NY 10021

Correspondence to Bai Lu: bailu{at}mail.nih.gov

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.

Abbreviations used in this paper: -BTX, -bungarotoxin; AChR, acetylcholine receptor; BDNF, brain-derived neurotrophic factor; CNS, central nervous system; COM, center of mass; ESC, evoked synaptic current; LTP, long-term potentiation; mBDNF, mature BDNF; MMP, matrix metalloprotease; NMJ, neuromuscular junction; p75^NTR, pan-neurotrophin receptor p75; ROI, region of interest; SSC, spontaneous synaptic current; Trk, tropomyosin-related kinase.

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This article has been cited by other articles:

• Short, B. (2009). BDNF sends mixed signals. JCB 185: 566-566 [Full Text]  

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