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

Area of Science:

• Neuroscience
• Synaptic Plasticity
• Molecular Biology

Background:

• Postsynaptic cells modulate presynaptic function via retrograde signals.
• Neuromuscular synapses exhibit activity-dependent synaptic depression.
• The role of pro-neurotrophins in synaptic modulation is under investigation.

Purpose of the Study:

• To investigate the role of pro-brain-derived neurotrophic factor (BDNF) as a retrograde signal at developing neuromuscular synapses.
• To elucidate the mechanism by which pro-BDNF modulates synaptic efficacy and terminal morphology.
• To determine the influence of proteolytic conversion on pro-BDNF's signaling function.

Main Methods:

• Electrophysiological recordings of synaptic activity.
• Application of pro-BDNF and metalloprotease inhibitors.
• Genetic manipulation of pro-BDNF expression and receptor inhibition (p75(NTR)).

Main Results:

• Pro-BDNF application decreased synaptic efficacy and induced presynaptic terminal retraction, mediated by p75(NTR).
• Cleavable pro-BDNF elicited synaptic potentiation, while uncleavable pro-BDNF caused depression.
• Metalloprotease inhibition enhanced activity-dependent synaptic depression, and inhibition of p75(NTR) or BDNF blocked these effects.

Conclusions:

• Pro-BDNF serves as a dual-acting retrograde signal at neuromuscular synapses.
• Proteolytic conversion of pro-BDNF by metalloproteases dictates its function as a positive or negative modulator.
• This mechanism regulates presynaptic terminal stabilization or elimination based on synaptic activity.