PDF(Pubmed)
Abstract：
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.
摘要：
异常tau蛋白与许多神经退行性疾病的病理学有关。转基因rTg4510小鼠表达高水平的人tau蛋白，其具有与17号染色体相关的P301L突变，该突变与伴有帕金森病的额颞叶痴呆相关。9个月大的时候,这些小鼠概括了人类tau蛋白病的关键特征，包括脑组织中过度磷酸化的tau和神经原纤维缠结（NFTs）的存在，神经元和突触的萎缩和丧失，和神经元的过度兴奋，以及认知缺陷。我们研究了这种人突变tau蛋白对神经元膜的影响，阈值下树突信号，和9个月大的rTg4510小鼠的III层额叶转基因（TG）锥体神经元的突触输入模式识别/区分，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。通过使用三维重建的形态学和这些细胞的电生理数据，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，突变tau蛋白不影响神经元膜的泄漏电阻和电容。TG神经元的计算机模型显示，相对于WT对照，沿着树突的体细胞金属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）的上升时间和半宽度仅有适度的变化。相比之下,在突变神经元的树突表面的所有区域中,模拟的亚阈值下树突状信号传播的速度检测到一致且统计学上显著的减慢.突触输入模式识别/区分的预测因子在模型TG神经元中保持不变。这表明tau病理学主要与突触连接的失败/丢失有关，而不是与受影响网络的神经元中神经元内突触整合的改变有关。
