Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA.
Neurobiol Aging. 2014 Jan;35(1):88-95. doi: 10.1016/j.neurobiolaging.2013.07.007. Epub 2013 Aug 7.
Abnormal neuronal excitability and impaired synaptic plasticity might occur before the degeneration and death of neurons in Alzheimer's disease (AD). To elucidate potential biophysical alterations underlying aberrant neuronal network activity in AD, we performed whole-cell patch clamp analyses of L-type (nifedipine-sensitive) Ca(2+) currents (L-VGCC), 4-aminopyridine-sensitive K(+) currents, and AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid) and NMDA (N-methyl-D-aspartate) currents in CA1, CA3, and dentate granule neurons in hippocampal slices from young, middle-age, and old 3xTgAD mice and age-matched wild type mice. 3xTgAD mice develop progressive widespread accumulation of amyloid β-peptide, and selective hyperphosphorylated tau pathology in hippocampal CA1 neurons, which are associated with cognitive deficits, but independent of overt neuronal degeneration. An age-related elevation of L-type Ca(2+) channel current density occurred in CA1 neurons in 3xTgAD mice, but not in wild type mice, with the magnitude being significantly greater in older 3xTgAD mice. The NMDA current was also significantly elevated in CA1 neurons of old 3xTgAD mice compared with in old wild type mice. There were no differences in the amplitude of K(+) or AMPA currents in CA1 neurons of 3xTgAD mice compared with wild type mice at any age. There were no significant differences in Ca(2+), K(+), AMPA, or NMDA currents in CA3 and dentate neurons from 3xTgAD mice compared with wild type mice at any age. Our results reveal an age-related increase of L-VGCC density in CA1 neurons, but not in CA3 or dentate granule neurons, of 3xTgAD mice. These findings suggest a potential contribution of altered L-VGCC to the selective vulnerability of CA1 neurons to tau pathology in the 3xTgAD mice and to their degeneration in AD patients.
阿尔茨海默病（AD）患者神经元变性和死亡前可能存在异常神经元兴奋性和突触可塑性障碍。为了阐明 AD 中异常神经元网络活动的潜在生物物理变化，我们对来自年轻、中年和老年 3xTgAD 小鼠和年龄匹配的野生型小鼠的海马切片 CA1、CA3 和齿状回神经元进行了全细胞膜片钳分析，检测 L 型（硝苯地平敏感）Ca2+电流（L-VGCC）、4-氨基吡啶敏感 K+电流以及 AMPA（2-氨基-3-（3-羟基-5-甲基异恶唑-4-基）丙酸）和 NMDA（N-甲基-D-天冬氨酸）电流。3xTgAD 小鼠会逐渐广泛积累淀粉样β肽，并在海马 CA1 神经元中出现选择性过度磷酸化的 tau 病理，这与认知缺陷有关，但与明显的神经元变性无关。在 3xTgAD 小鼠的 CA1 神经元中，L 型 Ca2+通道电流密度随年龄的增长而升高，但在野生型小鼠中则没有，而在老年 3xTgAD 小鼠中升高的幅度更大。与老年野生型小鼠相比，老年 3xTgAD 小鼠的 CA1 神经元中的 NMDA 电流也显著升高。在任何年龄，3xTgAD 小鼠 CA1 神经元的 K+或 AMPA 电流幅度与野生型小鼠相比均无差异。在任何年龄，3xTgAD 小鼠的 CA3 和齿状神经元的 Ca2+、K+、AMPA 或 NMDA 电流均与野生型小鼠无显著差异。我们的研究结果表明，在 3xTgAD 小鼠的 CA1 神经元中存在与年龄相关的 L-VGCC 密度增加，但在 CA3 或齿状神经元中则没有。这些发现表明，L-VGCC 的改变可能导致 3xTgAD 小鼠的 CA1 神经元对 tau 病理的选择性易感性增加，并导致 AD 患者的神经元变性。
