Beckman Institute, University of Illinois at Urbana-Champaign, IL, USA.
Brain Res. 2010 Oct 8;1355:221-7. doi: 10.1016/j.brainres.2010.07.090. Epub 2010 Aug 2.
Fragile X Syndrome (FXS) is the most common form of inherited mental retardation. The neuroanatomical phenotype of adult FXS patients, as well as adult Fmr1 knockout (KO) mice, includes elevated dendritic spine density and a spine morphology profile in neocortex that resembles younger individuals. Developmental studies in mouse neocortex have revealed a dynamic phenotype that varies with age, especially during the period of synaptic pruning. Here we investigated the hippocampal dentate gyrus to determine if the FXS spine phenotype is similarly tied to periods of maturation and pruning in this brain region. We used high-voltage electron microscopy to characterize Golgi-stained spines along granule cell dendrites in Fmr1 KO and wildtype (WT) mouse dentate gyrus at postnatal days 15, 21, 30, and 60. In contrast to neocortex, dendritic spine density was higher in Fmr1 KO mice across development. Interestingly, neither genotype showed specific phases of synaptogenesis or pruning, potentially explaining the phenotypic differences from neocortex. Similarly, although the KO mice showed a more immature morphological phenotype overall than WT (higher proportion of thin headed spines, lower proportion of mushroom and stubby spines), both genotypes showed gradual development, rather than impairments during specific phases of maturation. Finally, spine length showed a complex developmental pattern that differs from other brain regions examined, suggesting dynamic regulation by FMRP and other brain region-specific proteins. These findings shed new light on FMRP's role in development and highlight the need for new techniques to further understand the mechanisms by which FMRP affects synaptic maturation.
脆性 X 综合征（FXS）是最常见的遗传性智力障碍形式。成年 FXS 患者和成年 Fmr1 敲除（KO）小鼠的神经解剖表型包括树突棘密度升高，以及新皮质中的棘突形态与年轻人相似。在小鼠新皮质中的发育研究揭示了一种随年龄变化的动态表型，尤其是在突触修剪期间。在这里，我们研究了海马齿状回，以确定 FXS 棘突表型是否与该脑区的成熟和修剪时期相似。我们使用高压电子显微镜来描述 Fmr1 KO 和野生型（WT）小鼠齿状回颗粒细胞树突上的高尔基染色棘突，在出生后第 15、21、30 和 60 天。与新皮质不同，在整个发育过程中，Fmr1 KO 小鼠的树突棘密度更高。有趣的是，两种基因型都没有表现出特定的突触发生或修剪阶段，这可能解释了与新皮质的表型差异。同样，尽管 KO 小鼠的形态表型总体上比 WT 更不成熟（大头棘突的比例较高，蘑菇和短粗棘突的比例较低），但两种基因型都表现出逐渐的发育，而不是在特定的成熟阶段出现损伤。最后，棘突长度表现出一种与其他检查脑区不同的复杂发育模式，这表明 FMRP 及其它脑区特异性蛋白的动态调节。这些发现为 FMRP 在发育中的作用提供了新的认识，并强调需要新的技术来进一步了解 FMRP 影响突触成熟的机制。
