重复经颅磁刺激对阿尔茨海默病小鼠海马齿状回钾离子通道的影响

Effect of transcranial magnetic stimulation on potassium channels in the dentate gyrus of the hippocampus of Alzheimer’s disease mice

背景:经颅磁刺激已经被用于治疗阿尔茨海默病,但其机制尚未完全明确。目的:分析重复经颅磁刺激对阿尔茨海默病小鼠海马齿状回神经兴奋性的作用机制。方法:采用随机数字表法,将16只C57BL/6小鼠随机分为对照组(n=8)、对照+磁刺激组(n=8),将16只APP/PS1小鼠随机分为痴呆组(n=8)、痴呆+磁刺激组(n=8),对照+磁刺激组与痴呆+磁刺激组给予重复经颅磁刺激,2 h/d,连续刺激14 d。磁刺激结束后,采用水迷宫实验检测小鼠认知能力,全细胞膜片钳技术采集动作电位,分析阿尔茨海默病对动作电位的影响;全细胞膜片钳技术采集钾离子通道电流,分析其动力学特性对神经兴奋性的作用。结果结论:①水迷宫实验结果显示,正常小鼠接受重复经颅磁刺激后能够更加精准地找到确定原平台位置,阿尔茨海默病导致小鼠学习记忆能力下降,找到平台次数下降,海马齿状回神经元退化,而重复经颅磁刺激可提高阿尔茨海默病小鼠的学习记忆能力;②全细胞膜片钳技术检测结果显示,重复经颅磁刺激能够使阿尔茨海默病小鼠神经元更容易发生去极化,使神经元更易兴奋;③钾离子通道电流分析结果显示,阿尔茨海默病使得瞬时外向钾通道半数激活电压增大,失活曲线向着去极化方向偏移,复活时间常数延长,使得延迟整流钾通道激活曲线向着去极化的方向偏移,而重复经颅磁刺激干预延迟了钾离子通道的打开与关闭,抑制了细胞内钾离子的外流,使得细胞内保持较高浓度K^(+),提高了神经元兴奋性;④结果表明,重复经颅磁刺激可能通过提高海马齿状回颗粒神经元兴奋性来缓解认知能力的衰退。

BACKGROUND:Transcranial magnetic stimulation has been used in the treatment of Alzheimer’s disease,but its mechanism has not been fully clarified.OBJECTIVE:To explore the mechanism of repetitive transcranial magnetic stimulation to increase neural excitability in mice with Alzheimer’s disease.METHODS:Sixteen C57BL/6 mice were randomized into control group(n=8)and control+magnetic stimulation group(n=8).Another 16 APP/PS1 mice were randomized into dementia group(n=8)and dementia+magnetic stimulation group(n=8).Mice in the two magnetic stimulation groups were given repetitive transcranial magnetic stimulation,2 hours daily,for 14 continuous days.The water maze was then used to detect the cognitive function of mice.Whole-cell membrane-clamp technique was used to collect action potentials and analyze the effect of Alzheimer’s disease on action potentials;and the potassium channel currents were collected and analyzed for the role of their kinetic properties on neural excitability.RESULTS AND CONCLUSION:The results of Morris water maze showed that normal mice could find and determine the original platform more accurately after receiving repetitive transcranial magnetic stimulation,while Alzheimer’s disease led to a decrease in the learning and memory ability of mice,a decrease in the number of times they found the platform,and a degeneration of neurons in the hippocampal dentate gyrus.Repetitive transcranial magnetic stimulation could improve the learning and memory ability of mice with Alzheimer’s disease.Whole-cell membrane clamp technique assay showed that repetitive transcranial magnetic stimulation could trigger neuronal depolarization and enhance neuronal excitability in Alzheimer’s disease mice.Analysis of potassium channel currents showed that Alzheimer’s disease caused an increase in the transient outward potassium channel half-activation voltage.The inactivation curve was shifted in the direction of depolarization and the resuscitation time constant was prolonged,causing the delayed rectifier potassium channel activation curve to be shifted in the direction of depolarization.Whereas repetitive transcranial magnetic stimulation delayed the opening and closing of the potassium channel and inhibit the efflux of intracellular potassium ions,which resulted in the retention of a higher intracellular potassium concentration and increased neuronal excitability.To conclude,repetitive transcranial magnetic stimulation may alleviate cognitive decline by increasing neuronal excitability in the hippocampal dentate gyrus.