Presynaptic NCAM Is Required for Motor Neurons to Functionally Expand Their Peripheral Field of Innervation in Partially Denervated Muscles
Presynaptic NCAM Is Required for Motor Neurons to Functionally Expand Their Peripheral Field of Innervation in Partially Denervated Muscles
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DOI：
10.1523/jneurosci.0697-14.2014
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发表时间：
2014-08-06
影响因子：
5.3
通讯作者：
Rafuse, Victor F.
中科院分区：
文献类型：
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作者：
Chipman, Peter H.;Schachner, Melitta;Rafuse, Victor F.
通过部分去神经支配缺少突触前神经黏附分子(HB9(Cre)NCAM(Flx))的小鼠比目鱼肌，探讨运动神经元中神经细胞黏附分子(NCAM)表达在轴突萌发和代偿性神经再支配中的作用。与以前的研究一致，野生型(NCAM(+/+))小鼠的肌肉收缩力在移除75%的运动神经后2周完全恢复，因为运动单位的大小增加了2.5倍。相比之下，HB9(Cre)NCAM(Flx)小鼠同样失神经的肌肉未能恢复由于部分失神经而失去的力量，因为运动单位的大小没有改变。解剖分析表明，Hb9creNCAMflx小鼠部分失神经后1~4周，50%的比目鱼肌终板完全失神经，25%的比目鱼肌终板部分再支配。在HB9(Cre)NCAM(Flx)小鼠中，突触小泡(SVS)保留在突触外区域，而不是像正常情况下那样分布到新支配的神经肌肉接头(NMJ)。电生理分析显示，在部分失神经的HB9(Cre)NCAM(Flx)比目鱼肌中有两类NMJ，一类是高(成熟)量子含量的，另一类是低(未成熟)量子含量的。HB9(Cre)NCAM(Flx)芽中的突触外SVs与L型电压依赖性钙通道(L-VDCC)免疫反应相关，并维持一种未成熟的L-VDCC依赖的循环表型。此外，急性硝苯地平治疗增强了新生NMJ的神经传递，而在突触巩固期间慢性腹腔注射硝苯地平在没有突触前NCAM的情况下促进了功能运动单位的扩张。我们认为，突触前NCAM通过调节L-VDCCs，在SV周期和突触区域的功能扩展之间架起了一条重要的桥梁。
The function of neural cell adhesion molecule (NCAM) expression in motor neurons during axonal sprouting and compensatory reinnervation was explored by partially denervating soleus muscles in mice lacking presynaptic NCAM (Hb9(cre)NCAM(flx)). In agreement with previous studies, the contractile force of muscles in wild-type (NCAM(+/+)) mice recovered completely 2 weeks after 75% of the motor innervation was removed because motor unit size increased by 2.5 times. In contrast, similarly denervated muscles in Hb9(cre)NCAM(flx) mice failed to recover the force lost due to the partial denervation because motor unit size did not change. Anatomical analysis indicated that 50% of soleus end plates were completely denervated 1-4 weeks post-partial denervation in Hb9creNCAMflx mice, while another 25% were partially reinnervated. Synaptic vesicles (SVs) remained at extrasynaptic regions in Hb9(cre)NCAM(flx) mice rather than being distributed, as occurs normally, to newly reinnervated neuromuscular junctions (NMJs). Electrophysiological analysis revealed two populations of NMJs in partially denervated Hb9(cre)NCAM(flx) soleus muscles, one with high (mature) quantal content, and another with low (immature) quantal content. Extrasynaptic SVs in Hb9(cre)NCAM(flx) sprouts were associated with L-type voltage-dependent calcium channel (L-VDCC) immunoreactivity and maintained an immature, L-VDCC-dependent recycling phenotype. Moreover, acute nifedipine treatment potentiated neurotransmission at newly sprouted NMJs, while chronic intraperitoneal treatment with nifedipine during a period of synaptic consolidation enhanced functional motor unit expansion in the absence of presynaptic NCAM. We propose that presynaptic NCAM bridges a critical link between the SV cycle and the functional expansion of synaptic territory through the regulation of L-VDCCs.