摘要
我们以前报道了大电导率钙激活的钾(big-K,BK)通道的活性受到皮质锥体细胞中细胞内Aβ的抑制,且该抑制被3xTg老年痴呆模型小鼠中的支架蛋白Homer1a所逆转。已知,Homer1a也是因生理性光刺激(PS)被表达的。因此PS也可能逆转Aβ诱导的BK通道抑制而改善3xTg小鼠的认知能力。我们测试了其可能性。每日6小时持续4周的PS(频率,2 Hz;工作时间,约1/10;亮度,300lx)的长期应用改善了3xTg小鼠的与语境和声调相关的恐惧记忆,也较小程度地改善了其在Morris水迷宫中的表现。PS后,海马长期增强作用也被提高。环带皮层锥体细胞和侧杏仁体主细胞中的BK通道活性(在3xTg小鼠中被抑制)被促进。同时,神经元兴奋性(在3xTg小鼠中被提高)恢复至控制水平。BK通道和支架蛋白Homer1a的基因表达在3xTg小鼠中减少,并被PS逆转。已知,Homer1a是一种活性依赖性的可诱导的即时的早期基因产物。我们以前的发现始终显示:电刺激诱导的Homer1a促进了BK通道。通过敲除Homer1a,我们发现现在PS诱导的BK通道促进作用是Homer1a表达介导的。因此,我们推测PS可能成为老年痴呆的非侵入性治疗手段。
关键词: 老年痴呆,BK通道,认知能力改善,兴奋性,Homer1,光刺激。
Current Alzheimer Research
Title:Cognitive Improvement by Photic Stimulation in a Mouse Model of Alzheimer’s Disease
Volume: 12 Issue: 9
Author(s): Yu Zhang, Furong Wang, Xianwen Luo, Li Wang, Peng Sun, Min Wang, Yongsheng Jiang, Jingyu Zou, Osamu Uchiumi, Ryo Yamamoto and Tokio Sugai, Kenji Yamamoto and Nobuo Kato
Affiliation:
关键词: 老年痴呆,BK通道,认知能力改善,兴奋性,Homer1,光刺激。
摘要: We previously reported that activity of the large conductance calcium-activated potassium (big-K, BK) channel is suppressed by intracellular Aβ in cortical pyramidal cells, and that this suppression was reversed by expression of the scaffold protein Homer1a in 3xTg Alzheimer’s disease model mice. Homer1a is known to be expressed by physiological photic stimulation (PS) as well. The possibility thus arises that PS also reverses Aβ-induced suppression of BK channels, and thereby improves cognition in 3xTg mice. This possibility was tested here. Chronic application of 6-hour-long PS (frequency, 2 Hz; duty cycle, about 1/10; luminance, 300 lx) daily for 4 weeks improved contextual and tone-dependent fear memory in 3xTg mice and, to a lesser extent, Morris water maze performance as well. Hippocampal long-term potentiation was also enhanced after PS. BK channel activity in cingulate cortex pyramidal cells and lateral amygdalar principal cells, suppressed in 3xTg mice, were facilitated. In parallel, neuronal excitability, elevated in 3xTg mice, was recovered to the control level. Gene expression of BK channel, as well as that of the scaffold protein Homer1a, was found decreased in 3xTg mice and reversed by PS. It is known that Homer1a is an activity-dependently inducible immediate early gene product. Consistently, our previous findings showed that Homer1a induced by electrical stimulation facilitated BK channels. By using Homer1a knockouts, we showed that the present PS-induced BK channel facilitation is mediated by Homer1a expression. We thus propose that PS might be potentially useful as a non-invasive therapeutic measure against Alzheimer’s disease.
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Yu Zhang, Furong Wang, Xianwen Luo, Li Wang, Peng Sun, Min Wang, Yongsheng Jiang, Jingyu Zou, Osamu Uchiumi, Ryo Yamamoto and Tokio Sugai, Kenji Yamamoto and Nobuo Kato , Cognitive Improvement by Photic Stimulation in a Mouse Model of Alzheimer’s Disease, Current Alzheimer Research 2015; 12 (9) . https://dx.doi.org/10.2174/1567205012666150710115755
DOI https://dx.doi.org/10.2174/1567205012666150710115755 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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