PDF(Pubmed)
Abstract：
Loss-of-function mutations in the progranulin (GRN) gene are an autosomal dominant cause of Frontotemporal Dementia (FTD). These mutations typically result in haploinsufficiency of the progranulin protein. Grn+/- mice provide a model for progranulin haploinsufficiency and develop FTD-like behavioral abnormalities by 9-10 months of age. In previous work, we demonstrated that Grn+/- mice develop a low dominance phenotype in the tube test that is associated with reduced dendritic arborization of layer II/III pyramidal neurons in the prelimbic region of the medial prefrontal cortex (mPFC), a region key for social dominance behavior in the tube test assay. In this study, we investigated whether progranulin haploinsufficiency induced changes in dendritic spine density and morphology. Individual layer II/III pyramidal neurons in the prelimbic mPFC of 9-10 month old wild-type or Grn+/- mice were targeted for iontophoretic microinjection of fluorescent dye, followed by high-resolution confocal microscopy and 3D reconstruction for morphometry analysis. Dendritic spine density in Grn+/- mice was comparable to wild-type littermates, but the apical dendrites in Grn+/- mice had a shift in the proportion of spine types, with fewer stubby spines and more thin spines. Additionally, apical dendrites of Grn+/- mice had longer spines and smaller thin spine head diameter in comparison to wild-type littermates. These changes in spine morphology may contribute to altered circuit-level activity and social dominance deficits in Grn+/- mice.
摘要：
前颗粒蛋白（GRN）基因的功能丧失突变是额颞叶痴呆（FTD）的常染色体显性原因。这些突变通常导致颗粒体蛋白原蛋白的单倍性不足。Grn+/-小鼠提供了颗粒蛋白前体单倍性功能不全的模型,并在9-10月龄时发展FTD样行为异常。在以前的工作中,我们证明了Grn+/-小鼠在试管试验中发展出低优势表型，这与内侧前额叶皮质（mPFC）的边缘区II/III层锥体神经元的树突乔化减少有关，试管试验中社会支配行为的区域关键。在这项研究中,我们调查了颗粒原蛋白单倍性不足是否引起树突棘密度和形态的变化。9-10个月大的野生型或Grn/-小鼠的前边缘mPFC中的个体II/III层锥体神经元被靶向用于离子电渗显微注射荧光染料，其次是高分辨率共聚焦显微镜和三维重建的形态分析。Grn+/-小鼠的树突状脊柱密度与野生型同窝动物相当，但是Grn+/-小鼠的顶端树突在脊柱类型的比例上发生了变化，有较少的短刺和较薄的刺。此外,与野生型同窝动物相比，Grn/-小鼠的顶端树突具有更长的棘和更小的细脊柱头直径。脊柱形态的这些变化可能导致Grn/-小鼠的回路水平活动和社交优势缺陷的改变。
