Klotho regulates CA1 hippocampal synaptic plasticity.
Klotho regulates CA1 hippocampal synaptic plasticity.
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DOI：
10.1016/j.neuroscience.2017.02.006
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发表时间：
2017-04-07
期刊：
影响因子：
3.3
通讯作者：
King GD
中科院分区：
文献类型：
--
作者：
Li Q;Vo HT;Wang J;Fox-Quick S;Dobrunz LE;King GD
全球klotho过度表达延长了寿命，而klotho缺乏则缩短了寿命。同样，Klotho蛋白的操纵也会反向调节认知功能。没有klotho的小鼠在2个月大之前就会出现快速的认知障碍。与此同时，过度表达klotho的成年小鼠表现出认知功能的增强，特别是在海马区依赖的任务中。Klotho的认知增强作用延伸到具有Klotho多态的人类，Klotho多态可以增加循环Klotho和执行功能。为了影响认知功能，Klotho可以在突触内或突触上作用，以调节突触的传递或可塑性。然而，Klotho是否位于突触还不清楚，对其对突触功能的影响也知之甚少。为了验证这一点，我们对海马区进行了分离，并检测了突触前和突触后脑室中Klotho的表达。我们发现Klotho的丧失增强了5周龄CA1海马区突触可塑性的突触前和突触后的测量。然而，突触增强会迅速丧失，以至于到了7周时，当小鼠的认知受损时，与野生型对照组没有区别。Klotho过度表达的小鼠对突触可塑性没有早期生活影响，但在6个月大时检测到CA1海马长时程增强降低。总而言之，这些数据表明，klotho至少部分地通过调节海马区突触的可塑性来影响认知。
Global klotho overexpression extends lifespan while global klotho-deficiency shortens it. As well, klotho protein manipulations inversely regulate cognitive function. Mice without klotho develop rapid onset cognitive impairment before they are 2 months old. Meanwhile, adult mice overexpressing klotho show enhanced cognitive function, particularly in hippocampal-dependent tasks. The cognitive enhancing effects of klotho extend to humans with a klotho polymorphism that increases circulating klotho and executive function. To affect cognitive function, klotho could act in or on the synapse to modulate synaptic transmission or plasticity. However, it is not yet known if klotho is located at synapses, and little is known about its effects on synaptic function. To test this, we fractionated hippocampi and detected klotho expression in both pre and post-synaptic compartments. We find that loss of klotho enhances both pre and post-synaptic measures of CA1 hippocampal synaptic plasticity at 5 weeks of age. However, a rapid loss of synaptic enhancement occurs such that by 7 weeks, when mice are cognitively impaired, there is no difference from wild-type controls. Klotho overexpressing mice show no early life effects on synaptic plasticity, but decreased CA1 hippocampal long-term potentiation was measured at 6 months of age. Together these data suggest that klotho affects cognition, at least in part, by regulating hippocampal synaptic plasticity.