Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing 100084, China.
Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing 100084, China.
Exp Gerontol. 2023 Oct 15;182:112309. doi: 10.1016/j.exger.2023.112309. Epub 2023 Oct 13.
Neuronal hyperactivity is a key abnormality in early stage Alzheimer's disease (AD). Medial entorhinal cortex (mEC) plays a vital role in memory function and is affected early in AD. Growing evidence indicates benefits of regular exercise on memory and cognitive function in humans with AD, although, the underlying mechanisms are not clear. Therefore, this study was designed to test the effects of 16 weeks treadmill exercise on spatial learning memory and the underlying cellular mechanisms in 6-month-old 3xTg-AD mice. Whole-cell patch clamp was used to examine neuronal intrinsic excitability, spontaneous excitatory postsynaptic currents (sEPSCs) and spontaneous inhibitory postsynaptic currents (sIPSCs) of mEC layer II/III pyramidal neurons in the following groups: wild type (WT + sham), 3xTg-AD (AD+sham), WT receiving exercise (WT + Ex), and AD receiving exercise (AD+Ex). We found that at a behavioral level, treadmill exercise decreased working memory errors in radial arm maze (RAM) test in 6-month-old AD mice. At a cellular level, we found that treadmill exercise prevented the abnormal increase in mEC pyramidal neuron input resistance and action potential firing in 6-month-old 3xTg-AD mice compared with WT + sham and AD+Ex mice; further, sEPSC amplitude and frequency were normal in AD+Ex but overactive in AD+sham; additionally, GABAergic inhibition was normal in AD+Ex mice but reduced in AD+sham. In conclusion, our results indicate that treadmill exercise improves spatial learning memory and prevents network hyperexcitability in mEC by reducing pyramidal neuronal intrinsic excitability and normalizing excitatory and inhibitory synaptic transmission in 3xTg-AD mice.
神经元活动过度是早期阿尔茨海默病（AD）的一个关键异常。内嗅皮层（mEC）在记忆功能中起着至关重要的作用，并且在 AD 中很早就受到影响。越来越多的证据表明，有规律的运动对 AD 患者的记忆和认知功能有益，尽管其潜在机制尚不清楚。因此，本研究旨在测试 16 周跑步机运动对 6 月龄 3xTg-AD 小鼠空间学习记忆及其潜在细胞机制的影响。全细胞膜片钳技术用于检测以下各组 mEC 层 II/III 锥体神经元的神经元固有兴奋性、自发性兴奋性突触后电流（sEPSC）和自发性抑制性突触后电流（sIPSC）：野生型（WT+sham）、3xTg-AD（AD+sham）、接受运动的 WT（WT+Ex）和接受运动的 AD（AD+Ex）。我们发现，在行为水平上，跑步机运动可减少 6 月龄 AD 小鼠在放射臂迷宫（RAM）测试中的工作记忆错误。在细胞水平上，我们发现与 WT+sham 和 AD+Ex 小鼠相比，跑步机运动可防止 6 月龄 3xTg-AD 小鼠 mEC 锥体神经元输入电阻和动作电位放电的异常增加；此外，AD+Ex 中的 sEPSC 幅度和频率正常，但 AD+sham 中过度活跃；此外，AD+Ex 小鼠中的 GABA 能抑制正常，但 AD+sham 中减少。总之，我们的结果表明，跑步机运动通过降低锥体神经元固有兴奋性并使 3xTg-AD 小鼠的兴奋性和抑制性突触传递正常化，改善了 mEC 的空间学习记忆并防止了网络过度兴奋。
