Biosciences Institute, Newcastle University, Medical School, Framlington Place, Newcastle-upon-Tyne NE2 4HH, UK.
Institute of Clinical and Translational Research, Newcastle University, Medical School, Framlington Place, Newcastle-upon-Tyne NE2 4HH, UK.
Neurobiol Dis. 2021 Feb;149:105226. doi: 10.1016/j.nbd.2020.105226. Epub 2020 Dec 30.
Abnormal excitability in cortical networks has been reported in patients and animal models of Alzheimer's disease (AD), and other neurodegenerative conditions. Whether hyperexcitability is a core feature of alpha(α)-synucleinopathies, including dementia with Lewy bodies (DLB) is unclear. To assess this, we used two murine models of DLB that express either human mutant α-synuclein (α-syn) the hA30P, or human wild-type α-syn (hWT-α-syn) mice. We observed network hyperexcitability in vitro in young (2-5 months), pre-symptomatic transgenic α-syn mice. Interictal discharges (IIDs) were seen in the extracellular local field potential (LFP) in the hippocampus in hA30P and hWT-α-syn mice following kainate application, while only gamma frequency oscillations occurred in control mice. In addition, the concentration of the GABA receptor antagonist (gabazine) needed to evoke IIDs was lower in slices from hA30P mice compared to control mice. hA30P mice also showed increased locomotor activity in the open field test compared to control mice. Intracellular recordings from CA3 pyramidal cells showed a more depolarised resting membrane potential in hA30P mice. Quadruple immunohistochemistry for human α-syn, and the mitochondrial markers, porin and the complex IV enzyme cytochrome c oxidase subunit 1 (COX1) in parvalbumin (PV+)-expressing interneurons showed that 25% of PV+ cells contained human α-syn in hA30P mice. While there was no change in PV expression, COX1 expression was significantly increased in PV+ cells in hA30P mice, perhaps reflecting a compensatory change to support PV+ interneuron activity. Our findings suggest that hippocampal network hyperexcitability may be an important early consequence of α-syn-mediated impairment of neuronal/synaptic function, which occurs without any overt loss of PV interneurons. The therapeutic benefit of targeting network excitability early in the disease stage should be explored with respect to α-synucleinopathies such as DLB.
皮质网络的异常兴奋性已在阿尔茨海默病（AD）患者和动物模型以及其他神经退行性疾病中报道。兴奋性过高是否是包括路易体痴呆（DLB）在内的α-突触核蛋白病的核心特征尚不清楚。为了评估这一点，我们使用了两种表达人类突变α-突触核蛋白（α-syn）的 DLB 小鼠模型，即 hA30P 或人类野生型α-突触核蛋白（hWT-α-syn）小鼠。我们观察到年轻（2-5 个月）、无症状转基因α-syn 小鼠在体外的网络过度兴奋。在 hA30P 和 hWT-α-syn 小鼠中，应用海人酸后，在海马的细胞外局部场电位（LFP）中观察到发作间期放电（IIDs），而在对照小鼠中仅发生伽马频带振荡。此外，在 hA30P 小鼠切片中，诱发 IIDs 所需的 GABA 受体拮抗剂（gabazine）浓度低于对照小鼠。与对照小鼠相比，hA30P 小鼠在旷场测试中也表现出更高的运动活性。CA3 锥体神经元的细胞内记录显示，hA30P 小鼠的静息膜电位更去极化。四重免疫组织化学染色用于检测人类α-syn 和线粒体标志物，孔蛋白和复合物 IV 酶细胞色素 c 氧化酶亚基 1（COX1）在表达 parvalbumin（PV+）的中间神经元中，发现 hA30P 小鼠中 25%的 PV+细胞含有人类α-syn。虽然 PV 表达没有变化，但 hA30P 小鼠中 PV+细胞的 COX1 表达显著增加，这可能反映了支持 PV+中间神经元活动的代偿性变化。我们的发现表明，海马网络过度兴奋可能是由α-syn 介导的神经元/突触功能障碍引起的重要早期后果，而没有任何明显的 PV 中间神经元丢失。针对疾病早期阶段的网络兴奋性的治疗益处应该在针对α-突触核蛋白病（如 DLB）方面进行探索。
