Arbat-Plana Ariadna, Cobianchi Stefano, Herrando-Grabulosa Mireia, Navarro Xavier, Udina Esther
Institute of Neurosciences, Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.
Institute of Neurosciences, Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.
Neuroscience. 2017 Jan 6;340:188-200. doi: 10.1016/j.neuroscience.2016.10.057. Epub 2016 Oct 29.
After peripheral nerve injury, transected fibers distal to the lesion are disconnected from the neuronal body. This results in target denervation but also massive stripping of the central synapses of axotomized motoneurons, disrupting spinal circuits. Even when axonal regeneration is successful, the non-specific target reinnervation and the limited rebuilding of spinal circuits impair functional recovery. Therefore, strategies aimed to preserve spinal circuits after nerve lesions may improve the functional outcome. Activity-dependent therapy in the form of early treadmill running reduces synaptic stripping, mainly of excitatory synapses, and the disorganization of perineuronal nets (PNNs) on axotomized motoneurons. The mechanism underlying these effects remains unknown, although the benefits of exercise are often attributed to an increase in the neurotrophin brain-derived neurotrophic factor (BDNF). In this study, tropomyosin-related kinase (TrkB) agonist and antagonist were administered to rats subjected to sciatic nerve injury in order to shed light on the role of BDNF. The maintenance of synapses on axotomized motoneurons induced by treadmill running was partially dependent on TrkB activation. Treatment with the TrkB agonist at a low dose, but not at a high dose, prevented the decrease of excitatory glutamatergic synapses, and both doses increased the density of inhibitory synapses. TrkB inactivation counteracted only some of the positive effects exerted by exercise after nerve injury, such as maintenance of excitatory synapses surrounding motoneurons. Therefore, specific regimes of physical exercise are a better strategy to attenuate the alterations that motoneurons suffer after axotomy than pharmacological modulation of the TrkB pathway.
外周神经损伤后，损伤部位远端的横断纤维与神经元主体断开连接。这不仅导致靶器官去神经支配，还会使轴突切断的运动神经元的中枢突触大量剥脱，破坏脊髓回路。即使轴突再生成功，非特异性的靶器官再支配以及脊髓回路的有限重建也会损害功能恢复。因此，旨在保留神经损伤后脊髓回路的策略可能会改善功能结局。早期跑步机跑步形式的活动依赖性疗法可减少突触剥脱，主要是兴奋性突触的剥脱，以及轴突切断的运动神经元周围神经周网（PNN）的紊乱。尽管运动的益处通常归因于神经营养因子脑源性神经营养因子（BDNF）的增加，但这些作用的潜在机制仍然未知。在本研究中，将原肌球蛋白相关激酶（TrkB）激动剂和拮抗剂施用于坐骨神经损伤的大鼠，以阐明BDNF的作用。跑步机跑步诱导的轴突切断的运动神经元上突触的维持部分依赖于TrkB激活。低剂量而非高剂量的TrkB激动剂治疗可防止兴奋性谷氨酸能突触减少，且两种剂量均增加了抑制性突触的密度。TrkB失活仅抵消了神经损伤后运动所产生的一些积极作用，例如维持运动神经元周围的兴奋性突触。因此，特定的体育锻炼方案比TrkB途径的药物调节是减轻轴突切断后运动神经元所遭受改变的更好策略。
