Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Core Centre for Molecular Morphology, Section for Stereology and Microscopy, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Hippocampus. 2021 Apr;31(4):435-447. doi: 10.1002/hipo.23303. Epub 2021 Jan 19.
Down syndrome (DS), a genetic condition caused by triplication of chromosome 21, is characterized by alterations in various cognitive domains, including hippocampus-dependent memory functions, starting from early life stages. The major causes of intellectual disability in DS are prenatal neurogenesis alterations followed by impairment of dendritic development in early infancy. While there is evidence that the Ts65Dn mouse, the most widely used model of DS, exhibits dendritic alterations in adulthood, no studies are available regarding the onset of dendritic pathology. The goal of the current study was to establish whether this model exhibits early dendritic alterations in the hippocampus, a region whose function is severely damaged in DS. To this purpose, in Golgi-stained brains, we evaluated the dendritic arborization and dendritic spines of the granule cells of the hippocampal dentate gyrus in Ts65Dn mice aged 8 (P8) and 15 (P15) days. While P15 Ts65Dn mice exhibited a notably hypotrophic dendritic arbor and a reduced spine density, P8 mice exhibited a moderate reduction in the number of dendritic ramifications and no differences in spine density in comparison with their euploid counterparts. Both in P8 and P15 mice, spines were longer and had a longer neck, suggesting possible alterations in synaptic function. Moreover, P8 and P15 Ts65Dn mice had more thin spines and fewer stubby spines in comparison with euploid mice. Our study provides novel evidence on the onset of dendritic pathology, one of the causes of intellectual disability in DS, showing that it is already detectable in the dentate gyrus of Ts65Dn pups. This evidence strengthens the suitability of this model of DS as a tool to study dendritic pathology in DS and to test the efficacy of early therapeutic interventions aimed at ameliorating hippocampal development and, therefore, memory functions in children with DS.
唐氏综合征（DS）是一种由 21 号染色体三体引起的遗传疾病，其特征是在各种认知领域发生改变，包括海马依赖的记忆功能，从生命早期阶段开始。DS 患者智力障碍的主要原因是产前神经发生改变，随后在婴儿早期出现树突发育受损。虽然有证据表明，Ts65Dn 小鼠是最广泛使用的 DS 模型，在成年期表现出树突改变，但目前尚无关于树突病理发生的研究。本研究的目的是确定该模型是否在海马中表现出早期的树突改变，海马是 DS 中功能严重受损的区域。为此，我们在高尔基染色的大脑中评估了 Ts65Dn 小鼠 8 天（P8）和 15 天（P15）龄时海马齿状回颗粒细胞的树突分支和树突棘。虽然 P15 Ts65Dn 小鼠的树突分支明显萎缩，棘密度降低，但 P8 小鼠的树突分支数量中度减少，与正常二倍体相比，棘密度无差异。与正常二倍体相比，P8 和 P15 小鼠的棘均较长，棘颈较长，提示突触功能可能发生改变。此外，与正常二倍体小鼠相比，P8 和 P15 Ts65Dn 小鼠的细棘和短棘较多，而粗棘较少。本研究提供了关于树突病理发生的新证据，这是 DS 智力障碍的原因之一，表明它在 Ts65Dn 幼鼠的齿状回中已经可以检测到。这一证据加强了该 DS 模型作为研究 DS 中树突病理的工具的适用性，并测试了早期治疗干预以改善 DS 儿童海马发育和记忆功能的疗效。
