Hexanucleotide repeat expansion of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Synergies between loss of C9ORF72 functions and gain of toxicities from the repeat expansions contribute to C9ORF72-mediated pathogenesis. However, how loss of C9orf72 impacts neuronal and synaptic functions remains undetermined. Here, we showed that long-term potentiation at the dentate granule cells and long-term depression at the Schaffer collateral/commissural synapses at the area CA1 were reduced in the hippocampus of C9orf72 knockout mice. Using unbiased transcriptomic analysis, we identified that Klotho, a longevity gene, was selectively dysregulated in an age-dependent manner. Specifically, Klotho protein expression in the hippocampus of C9orf72 knockout mice was incorrectly enriched in the dendritic regions of CA1 with concomitant reduction in granule cell layer of dentate gyrus at 3-month of age followed by an accelerating decline during aging. Furthermore, adult hippocampal neurogenesis was reduced in C9orf72 knockout mice. Taken together, our data suggest that C9ORF72 is required for synaptic plasticity and adult neurogenesis in the hippocampus and Klotho deregulations may be part of C9ORF72-mediated toxicity.

中文翻译：

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在受损的突触可塑性和成年海马神经发生的C9orf72缺失小鼠中，长寿基因Klotho的表达失调。

C9ORF72的六核苷酸重复扩增是肌萎缩性侧索硬化和额颞痴呆的最常见遗传原因。C9ORF72功能丧失与重复扩增产生的毒性之间的协同作用有助于C9ORF72介导的发病机理。但是，C9orf72的损失如何影响神经元和突触功能仍未确定。在这里，我们显示了在C9orf72基因敲除小鼠的海马中，齿状颗粒细胞的长期增强作用和CA1区的Schaffer侧支/连合突触的长期抑制作用降低。使用无偏见的转录组学分析，我们确定了长寿基因Klotho以年龄依赖性方式选择性失调。特别，C9orf72基因敲除小鼠海马中的Klotho蛋白表达不正确地富集在CA1的树突区域中，伴随着3个月大时齿状回的颗粒细胞层减少，然后在衰老过程中加速下降。此外，C9orf72基因敲除小鼠的成年海马神经发生减少。两者合计，我们的数据表明，C9ORF72是突触可塑性和海马中成年神经发生所必需的，而Klotho失调可能是C9ORF72介导的毒性的一部分。