TrkB激酶活性维持成年神经肌肉接头处的突触功能和结构完整性。
TrkB kinase activity maintains synaptic function and structural integrity at adult neuromuscular junctions.
作者信息
Mantilla Carlos B, Stowe Jessica M, Sieck Dylan C, Ermilov Leonid G, Greising Sarah M, Zhang Chao, Shokat Kevan M, Sieck Gary C
机构信息
Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota; Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota; and
Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota;
出版信息
J Appl Physiol (1985). 2014 Oct 15;117(8):910-20. doi: 10.1152/japplphysiol.01386.2013. Epub 2014 Aug 28.
Activation of the tropomyosin-related kinase receptor B (TrkB) by brain-derived neurotrophic factor acutely regulates synaptic transmission at adult neuromuscular junctions (NMJs). The role of TrkB kinase activity in the maintenance of NMJ function and structure at diaphragm muscle NMJs was explored using a chemical-genetic approach that permits reversible inactivation of TrkB kinase activity in TrkB(F616A) mice by 1NMPP1. Inhibiting TrkB kinase activity for 7 days resulted in significant, yet reversible, impairments in neuromuscular transmission at diaphragm NMJs. Neuromuscular transmission failure following 2 min of repetitive phrenic nerve stimulation increased from 42% in control to 59% in 1NMPP1-treated TrkB(F616A) mice (P = 0.010). Recovery of TrkB kinase activity following withdrawal of 1NMPP1 treatment improved neuromuscular transmission (P = 0.006). Electrophysiological measurements at individual diaphragm NMJs documented lack of differences in quantal content in control and 1NMPP1-treated mice (P = 0.845). Morphological changes at diaphragm NMJs were modest following inhibition and recovery of TrkB kinase activity. Three-dimensional reconstructions of diaphragm NMJs revealed no differences in volume at motor end plates (labeled by α-bungarotoxin; P = 0.982) or presynaptic terminals (labeled by synaptophysin; P = 0.515). Inhibition of TrkB kinase activity by 1NMPP1 resulted in more compact NMJs, with increased apposition of presynaptic terminals and motor end plates (P = 0.017) and reduced fragmentation of motor end plates (P = 0.005). Recovery of TrkB kinase activity following withdrawal of 1NMPP1 treatment resulted in postsynaptic remodeling likely reflecting increased gutter depth (P = 0.007), without significant presynaptic changes. These results support an essential role for TrkB kinase activity in maintaining synaptic function and structural integrity at NMJs in the adult mouse diaphragm muscle.
脑源性神经营养因子激活原肌球蛋白相关激酶受体B（TrkB）可急性调节成年神经肌肉接头（NMJ）处的突触传递。利用化学遗传学方法探究了TrkB激酶活性在维持膈肌神经肌肉接头处NMJ功能和结构中的作用，该方法可通过1NMPP1使TrkB（F616A）小鼠的TrkB激酶活性可逆失活。抑制TrkB激酶活性7天导致膈肌神经肌肉接头处的神经肌肉传递出现显著但可逆的损伤。重复性膈神经刺激2分钟后的神经肌肉传递失败率从对照组的42%增加到1NMPP1处理的TrkB（F616A）小鼠的59%（P = 0.010）。停止1NMPP1处理后TrkB激酶活性的恢复改善了神经肌肉传递（P = 0.006）。对单个膈肌神经肌肉接头的电生理测量表明，对照组和1NMPP1处理的小鼠在量子含量上没有差异（P = 0.845）。在抑制和恢复TrkB激酶活性后，膈肌神经肌肉接头处的形态学变化不大。膈肌神经肌肉接头的三维重建显示，运动终板（用α-银环蛇毒素标记；P = 0.982）或突触前终末（用突触素标记；P = 0.515）的体积没有差异。1NMPP1抑制TrkB激酶活性导致神经肌肉接头更紧密，突触前终末与运动终板的并置增加（P = 0.017），运动终板的碎片化减少（P = 0.005）。停止1NMPP1处理后TrkB激酶活性的恢复导致突触后重塑，这可能反映了沟深度增加（P = 0.007），而突触前没有显著变化。这些结果支持TrkB激酶活性在维持成年小鼠膈肌神经肌肉接头处的突触功能和结构完整性中起重要作用。
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