Section on Neural Development and Plasticity, National Institute of Child Health and Human Development, and Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, Maryland 20892-3714, USA.
J Neurosci. 2013 Jun 12;33(24):9957-62. doi: 10.1523/JNEUROSCI.0163-13.2013.
During development, mammalian neuromuscular junctions (NMJs) transit from multiple-innervation to single-innervation through axonal competition via unknown molecular mechanisms. Previously, using an in vitro model system, we demonstrated that the postsynaptic secretion of pro-brain-derived neurotrophic factor (proBDNF) stabilizes or eliminates presynaptic axon terminals, depending on its proteolytic conversion at synapses. Here, using developing mouse NMJs, we obtained in vivo evidence that proBDNF and mature BDNF (mBDNF) play roles in synapse elimination. We observed that exogenous proBDNF promoted synapse elimination, whereas mBDNF infusion substantially delayed synapse elimination. In addition, pharmacological inhibition of the proteolytic conversion of proBDNF to mBDNF accelerated synapse elimination via activation of p75 neurotrophin receptor (p75(NTR)). Furthermore, the inhibition of both p75(NTR) and sortilin signaling attenuated synapse elimination. We propose a model in which proBDNF and mBDNF serve as potential "punishment" and "reward" signals for inactive and active terminals, respectively, in vivo.
在发育过程中，哺乳动物的神经肌肉接头（NMJ）通过轴突竞争从多神经支配过渡到单神经支配，其分子机制尚不清楚。先前，我们使用体外模型系统证明，脑源性神经营养因子前体（proBDNF）的突触后分泌可以稳定或消除突触前轴突末梢，具体取决于其在突触处的蛋白水解转化。在这里，我们使用发育中的小鼠 NMJ 获得了体内证据，表明 proBDNF 和成熟 BDNF（mBDNF）在突触消除中发挥作用。我们观察到外源性 proBDNF 促进了突触消除，而 mBDNF 的输注则大大延迟了突触消除。此外，通过激活 p75 神经营养因子受体（p75（NTR）），抑制 proBDNF 向 mBDNF 的蛋白水解转化加速了突触消除。此外，抑制 p75（NTR）和分选素信号均减弱了突触消除。我们提出了一个模型，其中 proBDNF 和 mBDNF 分别作为体内无活性和活性末端的潜在“惩罚”和“奖励”信号。
