Somogyi Attila, Wolf Ervin
Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Department of Emergency Medicine, University of Debrecen, Debrecen, Hungary.
Front Neurosci. 2021 Oct 18;15:721773. doi: 10.3389/fnins.2021.721773. eCollection 2021.
Abnormal tau proteins are involved in pathology of many neurodegenerative disorders. Transgenic rTg4510 mice express high levels of human tau protein with P301L mutation linked to chromosome 17 that has been associated with frontotemporal dementia with parkinsonism. By 9 months of age, these mice recapitulate key features of human tauopathies, including presence of hyperphosphorylated tau and neurofibrillary tangles (NFTs) in brain tissue, atrophy and loss of neurons and synapses, and hyperexcitability of neurons, as well as cognitive deficiencies. We investigated effects of such human mutant tau protein on neuronal membrane, subthreshold dendritic signaling, and synaptic input pattern recognition/discrimination in layer III frontal transgenic (TG) pyramidal neurons of 9-month-old rTg4510 mice and compared these characteristics to those of wild-type (WT) pyramidal neurons from age-matched control mice. Passive segmental cable models of WT and TG neurons were set up in the NEURON simulator by using three-dimensionally reconstructed morphology and electrophysiological data of these cells. Our computer simulations predict leakage resistance and capacitance of neuronal membrane to be unaffected by the mutant tau protein. Computer models of TG neurons showed only modest alterations in distance dependence of somatopetal voltage and current transfers along dendrites and in rise times and half-widths of somatic Excitatory Postsynaptic Potential (EPSPs) relative to WT control. In contrast, a consistent and statistically significant slowdown was detected in the speed of simulated subthreshold dendritic signal propagation in all regions of the dendritic surface of mutant neurons. Predictors of synaptic input pattern recognition/discrimination remained unaltered in model TG neurons. This suggests that tau pathology is primarily associated with failures/loss in synaptic connections rather than with altered intraneuronal synaptic integration in neurons of affected networks.
异常的tau蛋白参与了许多神经退行性疾病的病理过程。转基因rTg4510小鼠表达高水平的人类tau蛋白，该蛋白具有与17号染色体相关的P301L突变，这与伴有帕金森综合征的额颞叶痴呆有关。到9个月大时，这些小鼠重现了人类tau蛋白病的关键特征，包括脑组织中存在过度磷酸化的tau蛋白和神经原纤维缠结（NFTs）、神经元和突触的萎缩与丧失、神经元的过度兴奋以及认知缺陷。我们研究了这种人类突变tau蛋白对9个月大的rTg4510小鼠III层额叶转基因（TG）锥体神经元的神经元膜、阈下树突信号传导以及突触输入模式识别/辨别能力的影响，并将这些特征与年龄匹配的对照小鼠的野生型（WT）锥体神经元的特征进行了比较。通过使用这些细胞的三维重建形态和电生理数据，在NEURON模拟器中建立了WT和TG神经元的被动节段电缆模型。我们的计算机模拟预测，神经元膜的漏电电阻和电容不受突变tau蛋白的影响。TG神经元的计算机模型显示，相对于WT对照，沿树突的向体细胞电压和电流传递的距离依赖性以及体细胞兴奋性突触后电位（EPSP）的上升时间和半高宽仅发生了适度改变。相比之下，在突变神经元树突表面的所有区域，模拟的阈下树突信号传播速度出现了一致且具有统计学意义的减慢。模型TG神经元中突触输入模式识别/辨别能力的预测指标保持不变。这表明tau蛋白病主要与突触连接的失败/丧失有关，而不是与受影响网络中神经元内突触整合的改变有关。
