Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Rockville, USA.
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Neuropharmacology. 2020 Sep 1;174:108136. doi: 10.1016/j.neuropharm.2020.108136. Epub 2020 May 29.
In Parkinson's disease (PD) reduced levels of dopamine (DA) in the striatum lead to an abnormal circuit activity of the basal ganglia and an increased output through the substantia nigra pars reticulata (SNr) and the globus pallidus internal part. Synaptic inputs to the SNr shape its activity, however, the properties of glutamatergic synaptic transmission in this output nucleus of the basal ganglia in control and DA-depleted conditions are not fully elucidated. Using whole-cell patch-clamp recordings and pharmacological tools, we examined alterations in glutamatergic synaptic transmission in the SNr of a mouse model of PD, i.e. mice with unilateral 6-OHDA lesion of DA neurons in the substantia nigra pars compacta, as compared to control mice. We found that AMPA receptor (AMPAR)-mediated spontaneous and evoked excitatory postsynaptic currents (sEPSCs and eEPSCs) were not altered. The AMPA/NMDA ratio was significantly decreased in 6-OHDA-lesioned mice, suggesting an increased synaptic function of NMDA receptors (NMDARs) in DA-depleted mice. The decay kinetics of NMDAR-eEPSCs were faster in 6-OHDA-lesioned mice, indicating a possible change in the subunit composition of synaptic NMDARs. In control mice NMDAR-eEPSCs were mediated by diheteromeric NMDARs made of GluN2A, GluN2B and GluN2D. In 6-OHDA-lesioned mice the function of diheteromeric NMDARs containing either GluN2B or GluN2D was dramatically decreased, whereas the function of diheteromeric NMDARs made of GluN2A was preserved. Microinjections of an NMDAR antagonist into the SNr of 6-OHDA-lesioned mice resulted in significant improvements in spontaneous locomotion. This study identifies novel alterations occurring at excitatory synapses in the basal ganglia output nucleus following DA depletion. An increased synaptic NMDAR function, due to an altered subunit composition, might contribute to hyperactivation of SNr neurons in the DA depleted state and to motor impairments in PD.
在帕金森病 (PD) 中，纹状体中多巴胺 (DA) 水平降低导致基底节异常的电路活动，并通过黑质网状部 (SNr) 和苍白球内部分增加输出。突触输入到 SNr 塑造其活动，然而，在对照和 DA 耗竭条件下，该基底节输出核中的谷氨酸能突触传递的特性尚未完全阐明。使用全细胞膜片钳记录和药理学工具，我们检查了 PD 小鼠模型中 SNr 中谷氨酸能突触传递的变化，即单侧 6-OHDA 损伤黑质致密部 DA 神经元的小鼠与对照小鼠相比。我们发现 AMPA 受体 (AMPAR) 介导的自发性和诱发兴奋性突触后电流 (sEPSC 和 eEPSC) 没有改变。6-OHDA 损伤小鼠中 AMPA/NMDA 比值显著降低，表明 DA 耗竭小鼠中 NMDA 受体 (NMDAR) 的突触功能增加。6-OHDA 损伤小鼠中 NMDAR-eEPSC 的衰减动力学更快，表明突触 NMDAR 亚基组成可能发生变化。在对照小鼠中，NMDAR-eEPSC 由 GluN2A、GluN2B 和 GluN2D 组成的异二聚体 NMDAR 介导。在 6-OHDA 损伤小鼠中，含有 GluN2B 或 GluN2D 的异二聚体 NMDAR 的功能显著降低，而由 GluN2A 组成的异二聚体 NMDAR 的功能得以保留。将 NMDAR 拮抗剂微注射到 6-OHDA 损伤小鼠的 SNr 中可显著改善自发性运动。这项研究确定了在 DA 耗竭后基底节输出核中的兴奋性突触发生的新变化。由于亚基组成的改变，突触 NMDAR 功能增加可能导致 SNr 神经元在 DA 耗竭状态下过度激活，并导致 PD 中的运动障碍。
