Role of pro-brain-derived neurotrophic factor (proBDNF) to mature BDNF conversion in activity-dependent competition at developing neuromuscular synapses

Abstract

Formation of specific neuronal connections often involves competition between adjacent axons, leading to stabilization of the active terminal, while retraction of the less active ones. The underlying molecular mechanisms remain unknown. We show that activitydependent conversion of pro-brain-derived neurotrophic factor (proBDNF) to mature (m)BDNF mediates synaptic competition. Stimulation of motoneurons triggers proteolytic conversion of proBDNF to mBDNF at nerve terminals. In Xenopus nerve-muscle cocultures, in which two motoneurons innervate one myocyte, proBDNFp75 NTR signaling promotes retraction of the less active terminal, whereas mBDNF-tyrosine-related kinase B (TrkB) p75NTR (p75 neurotrophin receptor) facilitates stabilization of the active one. Thus, proBDNF and mBDNF may serve as potential "punishment" and "reward" signals for inactive and active terminals, respectively, and activity-dependent conversion of proBDNF to mBDNF may regulate synapse elimination. neuromuscular junction | pro-neurotrophin | synapse competition

Spontaneous Activity Drives Local Synaptic Plasticity In Vivo

“…ProBDNF/p75 NTR signaling was an attractive candidate since it has been shown to retrogradely depress synapses in an activity-dependent manner (neuromuscular junction: Yang et al, 2009a;Je et al, 2012;hippocampus: Woo et al, 2005;Yang et al, 2014). Furthermore, it is highly expressed during development in the hippocampus (Yang et al, 2009b), and it is known to be involved in synaptic competition and elimination (Je et al, 2012). To test the role of proBDNF/p75 NTR signaling in local plasticity and synaptic clustering, we first investigated whether synaptic depression induced by asynchronous stimulation (see : stimulation is triggered in response to distant spontaneous synaptic activity (12-24 mm) to decrease the local coactivity rate.…”

Matrix Metalloproteinase-9 as a Novel Player in Synaptic Plasticity and Schizophrenia: Table 1.

“…37,38 Furthermore, some of the candidate proteins that are implicated in schizophrenia have functional connections with either MMP-9 or MMP-9-interacting proteins, such as brain-derived neurotrophic factor (BDNF) and N-methyl-D-aspartate (NMDA) receptors, among others. 39,40 Another hallmark of schizophrenia is the dysfunction of dendritic spines. Several studies reported a reduction of spine density in cortical pyramidal neurons in schizophrenia (for review, see Moyer et al 41 ).…”

Mechanisms controlling neuromuscular junction stability

“…Nevertheless, the stabilization of the NMJ involves a synaptic competition that would be mediated by a ''punishment'' or Mechanisms controlling neuromuscular ''elimination'' signal produced by the post-synaptic cell, which causes the retraction of some of the terminals, as well as a ''protective'' or ''reward'' signal that stabilizes one terminal [70]. A hypothesis to explain synapse elimination has been the active versus inactive synapses involving a competitive process.…”

“…Whereas molecular cues involved in this process have remained poorly characterized so far, it has been recently shown that the activity-dependent conversion of pro-brainderived neurotrophic factor (proBDNF) to mature (m)BDNF mediates synaptic competition [70]. The activity of motor neurons will trigger the proteolytic conversion of proBDNF to mBDNF at nerve terminals whose respective roles are opposite: when two distinct motor neuron axons innervate one myocyte, proBDNF-p75(NTR) signaling promotes the retraction of the less active terminal, whereas mBDNF-tyrosine-related kinase B (TrkB) p75NTR facilitates the stabilization of the more active one.…”