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与疾病相关的KCNMA1变异在道病症小鼠模型中降低昼夜时钟的稳定性

Ria L Dinsdale¹, Cooper E Roache¹, Andrea L Meredith¹

¹Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.

The Journal of general physiology

|September 20, 2023

概括

编码BK通道的KCNMA1基因中的功能获取突变会损害小鼠的昼夜节律. 这些BK通道变化降低了节律的稳定性,改变了对光的反应,影响了日常行为.

科学领域:

神经科学是一个神经科学.
时间生物学时间生物学
遗传学遗传学是一个

背景情况:

KCNMA1基因编码大导电电压和激活 (BK) 通道.
BK通道调节神经元的发射,对昼夜行为节律至关重要.
人类KCNMA1通道病变与神经系统疾病有关,但它们对昼夜功能的影响尚不清楚.

研究的目的:

研究与人类疾病相关的KCNMA1通道变异对小鼠模型中昼夜行为的影响.
评估KCNMA1基因突变的功能增益 (GOF) 和功能丧失 (LOF) 是否会改变昼夜节律的强度和对光的反应.

主要方法:

三种具有明显KCNMA1突变的小鼠系的生成和行为评估:两个GOF (Kcnma1N999S/WT,Kcnma1D434G/D434G) 和一个LOF (Kcnma1H444Q/H444Q).
使用运行轮监测的运动运动活动,以分析昼夜参数,如振幅,周期和节律性.
对光脉冲的相位移动反应被评估,以评估昼夜钟的灵敏度和重新训练到新的光:黑暗周期.

主要成果:

这三个小鼠模型都保持了昼夜节律.
在GOF模型 (Kcnma1N999S/WT和Kcnma1D434G/D434G) 中,昼夜振幅降低,整体活动降低.
GOF模型显示了增强的光敏感性,更快地重新训练到新的光周期,并改变了相位转移反应,而LOF模型显示没有显著的昼夜变化.

结论:

通过GOF KCNMA1变体增加BK通道活动,减少昼夜时钟的稳定性.
改变的BK通道功能,特别是GOF,会影响昼夜节律对光等环境线索的敏感性.
这些发现强调了BK通道活动水平在维持稳定的昼夜行为方面的关键作用,并表明了与KCNMA1通道病变相关的神经系统疾病的潜在机制.

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