Suppression of a Neocortical Potassium Channel Activity by Intracellular Amyloid-β and Its Rescue with Homer1a
Suppression of a Neocortical Potassium Channel Activity by Intracellular Amyloid-β and Its Rescue with Homer1a
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DOI：
10.1523/jneurosci.6752-10.2011
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发表时间：
2011-08
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影响因子：
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通讯作者：
Kenji Yamamoto;Y. Ueta;Li Wang;R. Yamamoto;N. Inoue;K. Inokuchi;A. Aiba;H. Yonekura;N. Kato
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文献类型：
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作者：
Kenji Yamamoto;Y. Ueta;Li Wang;R. Yamamoto;N. Inoue;K. Inokuchi;A. Aiba;H. Yonekura;N. Kato
有人提出，在细胞外斑块形成之前，细胞内淀粉样蛋白-β (Aβ)会引发阿尔茨海默病（AD）的认知缺陷。在这里，我们报告细胞内Aβ如何影响神经元特性。通过全细胞膜片移液器和3xTg AD模型小鼠，将Aβ蛋白注射到大鼠和小鼠的新皮质锥体细胞中，细胞内固有积累Aβ。在大鼠中，细胞内应用含有低聚物和单体的混合a β1-42制剂，但不含a β1-40的单体制剂，扩大了spike宽度，并通过新皮质神经元中的电压依赖性Ca2+通道增加了Ca2+内流。这两种作用都被charybdotoxin（一种大电导Ca2+激活的K+ (BK)通道阻滞剂）和异海松酸（一种BK通道打开剂）所模拟和阻断。令人惊讶的是，增加的Ca2+内流是由延长的峰值持续时间引起的，而不是由Aβ1-42直接调节Ca2+通道引起的。a β1-42诱导的spike展宽被电休克（ECS）阻断，我们之前已经证明，这可以通过支架蛋白Homer1a的表达促进BK通道的打开。在幼年3xTg和野生小鼠中，我们证实了Aβ1-42的增宽作用，这一作用再次被肉毒杆菌毒素模拟和阻断，并被ECS阻断。在Homer1a敲除小鼠中，ECS未能阻断a - β1-42的作用。BK通道上的单通道记录支持这些结果。这些发现表明，细胞内a β1-42对BK通道的抑制可能是AD大脑早期功能障碍的关键机制，这可能通过Homer1a的活性依赖性表达来抵消。
It is proposed that intracellular amyloid-β (Aβ), before extracellular plaque formation, triggers cognitive deficits in Alzheimer disease (AD). Here we report how intracellular Aβ affects neuronal properties. This was done by injecting Aβ protein into rat and mouse neocortical pyramidal cells through whole-cell patch pipettes and by using 3xTg AD model mice, in which intracellular Aβ is accumulated innately. In rats, intracellular application of a mixed Aβ1-42 preparation containing both oligomers and monomers, but not a monomeric preparation of Aβ1-40, broadened spike width and augmented Ca2+ influx via voltage-dependent Ca2+ channels in neocortical neurons. Both effects were mimicked and occluded by charybdotoxin, a blocker of large-conductance Ca2+-activated K+ (BK) channels, and blocked by isopimaric acid, a BK channel opener. Surprisingly, augmented Ca2+ influx was caused by elongated spike duration, but not attributable to direct Ca2+ channel modulation by Aβ1-42. The Aβ1-42-induced spike broadening was blocked by electroconvulsive shock (ECS), which we previously showed to facilitate BK channel opening via expression of the scaffold protein Homer1a. In young 3xTg and wild mice, we confirmed spike broadening by Aβ1-42, which was again mimicked and occluded by charybdotoxin and blocked by ECS. In Homer1a knock-out mice, ECS failed to block the Aβ1-42 effect. Single-channel recording on BK channels supported these results. These findings suggest that the suppression of BK channels by intracellular Aβ1-42 is a possible key mechanism for early dysfunction in the AD brain, which may be counteracted by activity-dependent expression of Homer1a.