Klotho-deficient mice rapidly develop cognitive impairment and show some evidence of the onset of neurodegeneration. However, it is impossible to investigate the long-term consequences on the brain because of the dramatic shortening of lifespan caused by systemic klotho deficiency. As klotho expression is downregulated with advancing organismal age, understanding the mechanisms of klotho action is important for developing novel strategies to support healthy brain aging. Previously, we reported that klotho-deficient mice show enhanced long-term potentiation prior to the onset of cognitive impairment. To inform this unusual phenotype, herein, we examined neuronal structure and in vitro synaptic function. Our results indicate that klotho deficiency causes the population of dendritic spines to shift towards increased head diameter and decreased length consistent with mature, mushroom type spines. Multi-electrode array recordings from klotho-deficient neurons show increased synchronous firing and activity changes reflective of increased neuronal network activity. Supplementation of the neuronal growth media with recombinant shed klotho corrected some but not all of the activity changes caused by klotho deficiency. Last, in vivo we found that klotho-deficient mice have a decreased latency to induced seizure activity. Together these data show that klotho-deficient memory impairments are underpinned by structural and functional changes that may preclude ongoing normal cognition.

中文翻译：

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Klotho 缺陷影响神经元的脊柱形态和网络同步。

Klotho 缺陷小鼠迅速出现认知障碍，并显示出一些神经退行性病变的证据。然而，由于系统性克洛索缺乏症会导致寿命急剧缩短，因此不可能研究对大脑的长期影响。由于 klotho 表达随着机体年龄的增长而下调，因此了解 klotho 作用机制对于开发支持健康大脑衰老的新策略非常重要。此前，我们报道了 klotho 缺陷小鼠在认知障碍发作之前表现出增强的长期增强作用。为了了解这种不寻常的表型，我们在本文中检查了神经元结构和体外突触功能。我们的结果表明，klotho 缺陷导致树突棘群体向头部直径增加和长度减少的方向转变，这与成熟的蘑菇型树突棘一致。来自 klotho 缺陷神经元的多电极阵列记录显示同步放电和活动变化的增加反映了神经元网络活动的增加。向神经元生长培养基中添加重组脱落的 klotho 可纠正部分但不是全部由 klotho 缺乏引起的活性变化。最后，在体内，我们发现 klotho 缺陷小鼠诱导癫痫发作的潜伏期缩短。这些数据共同表明，klotho 缺陷性记忆障碍是由结构和功能变化造成的，这些变化可能会妨碍持续的正常认知。