Wang Li, Kang Huicong, Li Yongzhi, Shui Yuan, Yamamoto Ryo, Sugai Tokio, Kato Nobuo
Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan; China-Japan Friendship Hospital, Beijing 100029, China.
Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan; Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Neuropharmacology. 2015 May;92:8-15. doi: 10.1016/j.neuropharm.2014.12.033. Epub 2015 Jan 8.
We previously showed that activity of the large conductance calcium-activated potassium (Big-K; BK) channels is suppressed in 3xTg Alzheimer disease (AD) model mice. However, its behavioral significance is not known. In the present report, ventricular injection of the BK channel activator isopimaric acid (ISO) was conducted to examine whether BK channel activation ameliorates cognition in 3xTg mice. The novel object recognition (NOR) test revealed that chronic injection of ISO improved non-spatial memory in 3xTg mice. In the Morris water maze, the probe test demonstrated an improved spatial memory after ISO injection. Electrophysiological underpinnings of the ISO effect were then examined in slices obtained from the mice after behavior. At hippocampal CA1 synapses, the basic synaptic transmission was abnormally elevated and long-term potentiation (LTP) was partially suppressed in 3xTg mice. These were both recovered by ISO treatment. We then confirmed suppressed BK channel activity in 3xTg mice by measuring the half-width of evoked action potentials. This was also recovered by ISO treatment. We previously showed that the recovery of BK channel activity accompanies reduction of neuronal excitability in pyramidal cells. Here again, pyramidal cell excitability, as assessed by calculating the frequency of evoked spikes, was elevated in the 3xTg mouse and was normalized by ISO. ELISA experiments demonstrated an ISO-induced reduction of Aβ1-42 content in hippocampal tissue in 3xTg mice. The present study thus suggests a potential therapeutic utility of BK channel activators for AD.
我们之前发现，在3xTg阿尔茨海默病（AD）模型小鼠中，大电导钙激活钾通道（大钾通道；BK通道）的活性受到抑制。然而，其行为学意义尚不清楚。在本报告中，通过脑室注射BK通道激活剂异海松酸（ISO），来研究BK通道激活是否能改善3xTg小鼠的认知功能。新物体识别（NOR）试验表明，长期注射ISO可改善3xTg小鼠的非空间记忆。在莫里斯水迷宫试验中，探针试验显示注射ISO后空间记忆得到改善。然后，在行为学实验后的小鼠脑片中检测ISO作用的电生理基础。在海马CA1突触处，3xTg小鼠的基础突触传递异常增强，长时程增强（LTP）受到部分抑制。这些异常均通过ISO处理得到恢复。我们通过测量诱发动作电位的半高宽，证实了3xTg小鼠中BK通道活性受到抑制。这一抑制同样通过ISO处理得到恢复。我们之前发现，BK通道活性的恢复伴随着锥体细胞神经元兴奋性的降低。在此，通过计算诱发尖峰的频率评估，3xTg小鼠的锥体细胞兴奋性升高，而ISO使其恢复正常。ELISA实验表明，ISO可使3xTg小鼠海马组织中Aβ1-42的含量降低。因此，本研究提示BK通道激活剂对AD具有潜在的治疗作用。
