Fischer D Luke, Kemp Christopher J, Cole-Strauss Allyson, Polinski Nicole K, Paumier Katrina L, Lipton Jack W, Steece-Collier Kathy, Collier Timothy J, Buhlinger Daniel J, Sortwell Caryl E
Department of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503.
MD/PhD Program, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503.
J Neurosci. 2017 Jul 12;37(28):6786-6796. doi: 10.1523/JNEUROSCI.2060-16.2017. Epub 2017 Jun 12.
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is the most common neurosurgical treatment for Parkinson's disease motor symptoms. In preclinical models, STN DBS provides neuroprotection for substantia nigra (SN) dopamine neurons and increases BDNF in the nigrostriatal system and primary motor cortex. However, whether BDNF signaling in the SN participates in the neuroprotective effects of DBS remains unknown. We demonstrate that STN DBS in male rats activates signaling downstream of tropomyosin receptor kinase type B (trkB), namely, phosphorylation of Akt and ribosomal protein S6, in SN neurons. Long-term trkB blockade abolished STN DBS-mediated neuroprotection of SN neurons following progressive 6-hydroxydopamine lesion and was associated with decreased phosphorylated ribosomal protein S6 immunoreactivity. Acute trkB blockade in rats with stable nigrostriatal denervation attenuated the forelimb akinesia improvement normally induced by STN DBS. These results suggest that STN DBS increases BDNF-trkB signaling to contribute to the neuroprotective and symptomatic efficacy of STN DBS. Subthalamic nucleus deep brain stimulation (STN DBS) is increasingly used in mid- to late-stage Parkinson's disease (PD) but with an incomplete knowledge of its molecular mechanisms. STN DBS is neuroprotective against neurotoxicants in animal models and increases BDNF. This study is the first to show that BDNF signaling through the cognate tropomyosin receptor kinase type B (trkB) receptor occurs in substantia nigra pars compacta neurons and is required for neuroprotection. In addition, blockade of trkB unexpectedly reduced the functional benefit of STN DBS on a short timescale that is inconsistent with canonical trkB signaling pathways, suggesting a noncanonical role for trkB in STN DBS-mediated behavioral effects. Together, these data implicate trkB signaling in the symptomatic efficacy and disease-modifying potential of STN DBS.
丘脑底核（STN）的深部脑刺激（DBS）是治疗帕金森病运动症状最常用的神经外科手术方法。在临床前模型中，STN DBS为黑质（SN）多巴胺能神经元提供神经保护，并增加黑质纹状体系统和初级运动皮层中的脑源性神经营养因子（BDNF）。然而，SN中的BDNF信号是否参与DBS的神经保护作用仍不清楚。我们证明，雄性大鼠的STN DBS可激活SN神经元中肌钙蛋白受体激酶B型（trkB）下游的信号，即Akt和核糖体蛋白S6的磷酸化。长期阻断trkB可消除STN DBS介导的对渐进性6-羟基多巴胺损伤后SN神经元的神经保护作用，并与磷酸化核糖体蛋白S6免疫反应性降低有关。对黑质纹状体去神经稳定的大鼠进行急性trkB阻断，可减弱STN DBS通常诱导的前肢运动不能改善。这些结果表明，STN DBS增加BDNF-trkB信号，有助于STN DBS的神经保护和症状改善效果。丘脑底核深部脑刺激（STN DBS）越来越多地用于中晚期帕金森病（PD），但其分子机制尚不完全清楚。STN DBS在动物模型中对神经毒素具有神经保护作用，并可增加BDNF。本研究首次表明，通过同源肌钙蛋白受体激酶B型（trkB）受体的BDNF信号在黑质致密部神经元中发生，并且是神经保护所必需的。此外，阻断trkB意外地在短时间内降低了STN DBS的功能益处，这与经典的trkB信号通路不一致，提示trkB在STN DBS介导的行为效应中具有非经典作用。总之，这些数据表明trkB信号参与了STN DBS的症状改善效果和疾病修饰潜能。
