Structural and functional changes in tau mutant mice neurons are not linked to the presence of NFTs.
Structural and functional changes in tau mutant mice neurons are not linked to the presence of NFTs.
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DOI：
10.1016/j.expneurol.2009.07.029
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发表时间：
2010-06
影响因子：
5.3
通讯作者：
Luebke, J. I.
中科院分区：
文献类型：
--
作者：
Rocher, A. B.;Crimins, J. L.;Amatrudo, J. M.;Kinson, M. S.;Todd-Brown, M. A.;Lewis, J.;Luebke, J. I.
关键词：
在rTg 4510小鼠模型中，突变型人tau变体P301 L的表达导致神经元缠结（NFT）、神经元死亡和记忆障碍的发展，这让人想起在人tau蛋白病中观察到的病理学。在本研究中，我们研究了突变体tau蛋白表达对单个神经元的电生理和形态学的影响，使用全细胞膜片钳记录和生物胞素填充的锥体细胞从rTg 4510（TG）和野生型（WT）同窝小鼠制备的皮质切片。在TG细胞中，42%的细胞在索马胞体中含有明显的硫磺素-S阳性包涵体，被归类为NFT阳性（NFT+），而58%的细胞没有可辨别的包涵体，被归类为NFT阴性（NFT-）。TG细胞的静息膜电位（Vr）显著去极化（+8 mV），因此，诱发重复动作电位（AP）放电率也显著增加。此外，单个AP在TG细胞中的持续时间显着较短，并且由超极化引起的去极化电压偏转或“凹陷”的幅度显着较大。除了这些功能性电生理变化，TG细胞表现出显着的形态学改变，包括损失或显着萎缩的顶丛，减少树突的复杂性和长度，并减少棘密度。重要的是，NFT−和NFT+ TG细胞在形态学和电生理学特性方面是不可区分的。我们的观察结果表明，突变的tau蛋白的表达导致神经元的显着结构和功能变化，但这些变化的发生独立于成熟的NFT的形成。
In the rTg4510 mouse model, expression of the mutant human tau variant P301L leads to development of neurofibrillary tangles (NFTs), neuronal death, and memory impairment reminiscent of the pathology observed in human tauopathies. In the present study, we examined the effects of mutant tau expression on the electrophysiology and morphology of individual neurons using whole-cell patch clamp recordings and biocytin filling of pyramidal cells in cortical slices prepared from rTg4510 (TG) and wild-type (WT) littermate mice. Among the TG cells, 42% contained a clear Thioflavin-S positive inclusion in the soma and were categorized as NFT positive (NFT+), while 58% had no discernable inclusion and were categorized as NFT negative (NFT−). The resting membrane potential (Vr) was significantly depolarized (+8 mV) in TG cells, and as a consequence, evoked repetitive action potential (AP) firing rates were also significantly increased. Further, single APs were significantly shorter in duration in TG cells and the depolarizing voltage deflection or "sag" evoked by hyperpolarization was significantly greater in amplitude. In addition to these functional electrophysiological changes, TG cells exhibited significant morphological alterations, including loss or significant atrophy of the apical tuft, reduced dendritic complexity and length, and reduction in spine density. Importantly, NFT− and NFT+ TG cells were indistinguishable with regard to both morphological and electrophysiological properties. Our observations show that expression of mutated tau results in significant structural and functional changes in neurons, but that these changes occur independent of mature NFT formation.
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影响因子：
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