Abstract：
BACKGROUND: Neurotrophins are essential factors for neural growth and function; they play a crucial role in neurodegenerative diseases where their expression levels are altered. Our previous research has demonstrated changes in synaptic plasticity and neurotrophin expression levels in a pharmacological model of Huntington\'s disease induced by 3-nitropropionic acid (3-NP). In the 3- NP-induced HD model, corticostriatal Long Term Depression (LTD) was impaired, but neurotrophin-3 (NT-3) restored striatal LTD. This study delves into the NT-3-induced signaling pathways involved in modulating and restoring striatal synaptic plasticity in cerebral slices from 3-NPinduced striatal degeneration in mice in vivo.
METHODS: Phospholipase C (PLC), phosphatidylinositol-3-kinase (PI3K), and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways activated by NT-3 were analyzed by means of field electrophysiological recordings in brain slices from control and 3-NP treated in the presence of specific inhibitors of the signaling pathways.
RESULTS: Using specific inhibitors, PLC, PI3K, and MEK/ERK signaling pathways contribute to NT3-mediated plasticity modulation in striatal tissue slices recorded from control animals. However, in the neurodegeneration model induced by 3-NP, the recovery of striatal LTD induced by NT-3 was prevented only by the PLC inhibitor. Moreover, the PLC signaling pathway appeared to trigger downstream activation of the endocannabinoid system, evidenced by AM 251, an inhibitor of the CB1 receptor, also hindered NT-3 plasticity recovery.
CONCLUSIONS: Our finding highlights the specific involvement of the PLC pathway in the neuroprotective effects of NT-3 in mitigating synaptic dysfunction under neurodegenerative conditions.
METHODS: Phospholipase C (PLC), phosphatidylinositol-3-kinase (PI3K), and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways activated by NT-3 were analyzed by means of field electrophysiological recordings in brain slices from control and 3-NP treated in the presence of specific inhibitors of the signaling pathways.
RESULTS: Using specific inhibitors, PLC, PI3K, and MEK/ERK signaling pathways contribute to NT3-mediated plasticity modulation in striatal tissue slices recorded from control animals. However, in the neurodegeneration model induced by 3-NP, the recovery of striatal LTD induced by NT-3 was prevented only by the PLC inhibitor. Moreover, the PLC signaling pathway appeared to trigger downstream activation of the endocannabinoid system, evidenced by AM 251, an inhibitor of the CB1 receptor, also hindered NT-3 plasticity recovery.
CONCLUSIONS: Our finding highlights the specific involvement of the PLC pathway in the neuroprotective effects of NT-3 in mitigating synaptic dysfunction under neurodegenerative conditions.
摘要：
背景：神经营养蛋白是神经生长和功能的重要因素；它们在神经退行性疾病中起着至关重要的作用，其中它们的表达水平被改变。我们先前的研究已经证明了在3-硝基丙酸（3-NP）诱导的亨廷顿病药理学模型中突触可塑性和神经营养蛋白表达水平的变化。在3-NP诱导的HD模型中，皮质纹状体长期抑郁（LTD）受损，但是神经营养蛋白-3（NT-3）恢复了纹状体LTD。这项研究探讨了NT-3诱导的信号通路，该通路参与调节和恢复3-NP诱导的小鼠纹状体变性的脑切片中纹状体突触可塑性。
方法：磷脂酶C（PLC），磷脂酰肌醇-3-激酶(PI3K),和由NT-3激活的丝裂原激活的蛋白激酶（MEK）/细胞外信号调节激酶（ERK）途径通过在对照和3-NP存在的情况下处理的脑切片中的场电生理记录进行分析信号通路的特异性抑制剂。
结果：使用特异性抑制剂，PLC,PI3K,和MEK/ERK信号通路有助于在对照动物记录的纹状体组织切片中NT3介导的可塑性调节。然而,在3-NP诱导的神经变性模型中，仅通过PLC抑制剂阻止NT-3诱导的纹状体LTD的恢复。此外，PLC信号通路似乎触发内源性大麻素系统的下游激活，由AM251证明，CB1受体的抑制剂，也阻碍了NT-3塑性恢复。
结论：我们的发现强调了PLC通路在NT-3减轻神经退行性条件下突触功能障碍的神经保护作用中的具体参与。
方法：磷脂酶C（PLC），磷脂酰肌醇-3-激酶(PI3K),和由NT-3激活的丝裂原激活的蛋白激酶（MEK）/细胞外信号调节激酶（ERK）途径通过在对照和3-NP存在的情况下处理的脑切片中的场电生理记录进行分析信号通路的特异性抑制剂。
结果：使用特异性抑制剂，PLC,PI3K,和MEK/ERK信号通路有助于在对照动物记录的纹状体组织切片中NT3介导的可塑性调节。然而,在3-NP诱导的神经变性模型中，仅通过PLC抑制剂阻止NT-3诱导的纹状体LTD的恢复。此外，PLC信号通路似乎触发内源性大麻素系统的下游激活，由AM251证明，CB1受体的抑制剂，也阻碍了NT-3塑性恢复。
结论：我们的发现强调了PLC通路在NT-3减轻神经退行性条件下突触功能障碍的神经保护作用中的具体参与。
