Progranulin haploinsufficiency causes biphasic social dominance abnormalities in the tube test.
Progranulin haploinsufficiency causes biphasic social dominance abnormalities in the tube test.
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DOI：
10.1111/gbb.12300
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发表时间：
2016-07
期刊：
影响因子：
--
通讯作者：
Roberson ED
中科院分区：
文献类型：
--
作者：
Arrant AE;Filiano AJ;Warmus BA;Hall AM;Roberson ED
原颗粒蛋白(GRN)功能缺失突变是额颞叶痴呆(FTD)的主要常染色体显性原因，FTD是一种社会行为被扰乱的神经退行性疾病。原颗粒蛋白缺乏的小鼠，包括Grn+/−和Grn−/−，被用作由于Grn突变引起的FTD的模型，Grn+/−小鼠模拟具有Grn突变的FTD患者的原颗粒蛋白单倍体缺乏。GRN+/−小鼠在6个月龄时在试管试验中具有更高的社会优势，尽管这种表型在GRN−/−小鼠中尚未报道。在这项研究中，我们研究了原颗粒缺乏小鼠的试管试验表型如何随年龄变化，确定了它在几种测试条件下的稳定性，并探索了相关的细胞机制。我们观察到Grn+/−小鼠的双相社会优势异常：在6-8月龄时，Grn+/−小鼠比野生型小鼠更具优势，而在9月龄后，Grn+/−小鼠则不那么占优势。相反，GRn−/−小鼠没有表现出异常的社会优势，这表明原颗粒单倍体不足与完全原颗粒缺乏有不同的影响。GRn+/−小鼠的双相试管试验表型与杏仁核和前额叶皮质细胞信号和神经元形态的异常有关。6-9月龄GRn+/−小鼠杏仁核mTORC2/Akt信号增强，基底内侧杏仁核树突状突起增强，9-16月龄GRn+/−小鼠前皮质树突状突起减少。这些数据证明了GRN+/−小鼠试管试验优势地位的渐进性变化，并表明部分但不完全的原颗粒缺乏会扰乱小鼠的这种行为。
Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia (FTD), a neurodegenerative disorder in which social behavior is disrupted. Progranulin-insufficient mice, both Grn+/− and Grn−/−, are used as models of FTD due to GRN mutations, with Grn+/− mice mimicking the progranulin haploinsufficiency of FTD patients with GRN mutations. Grn+/− mice have increased social dominance in the tube test at 6 months of age, though this phenotype has not been reported in Grn−/− mice. In this study, we investigated how the tube test phenotype of progranulin-insufficient mice changes with age, determined its robustness under several testing conditions, and explored associated cellular mechanisms. We observed biphasic social dominance abnormalities in Grn+/− mice: at 6–8 months, Grn+/− mice were more dominant than wild-type littermates, while after 9 months of age, Grn+/− mice were less dominant. In contrast, Grn−/− mice did not exhibit abnormal social dominance, suggesting that progranulin haploinsufficiency has distinct effects from complete progranulin deficiency. The biphasic tube test phenotype of Grn+/− mice was associated with abnormal cellular signaling and neuronal morphology in the amygdala and prefrontal cortex. At 6–9 months, Grn+/− mice exhibited increased mTORC2/Akt signaling in the amygdala and enhanced dendritic arbors in the basomedial amygdala, and at 9–16 months Grn+/− mice exhibited diminished basal dendritic arbors in the prelimbic cortex. These data demonstrate a progressive change in tube test dominance in Grn+/− mice and show that partial, but not complete progranulin deficiency disrupts this behavior in mice.
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