Effects of individual segmental trisomies of human chromosome 21 syntenic regions on hippocampal long-term potentiation and cognitive behaviors in mice.

As the genomic basis for Down syndrome (DS), human trisomy 21 is the most common genetic cause of intellectual disability in children and young people. The genomic regions on human chromosome 21 (Hsa21) are syntenic to three regions in the mouse genome, located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. Recently, we have developed three new mouse models using chromosome engineering carrying the genotypes of Dp(10)1Yey/+, Dp(16)1Yey/+, or Dp(17)1Yey/+, which harbor a duplication spanning the entire Hsa21 syntenic region on Mmu10, Mmu16, or Mmu17, respectively. In this study, we analyzed the hippocampal long-term potentiation (LTP) and cognitive behaviors of these models. Our results show that, while the genotype of Dp(17)1Yey/+ results in abnormal hippocampal LTP, the genotype of Dp(16)1Yey/+ leads to both abnormal hippocampal LTP and impaired learning/memory. Therefore, these mutant mice can serve as powerful tools for further understanding the mechanism underlying cognitively relevant phenotypes associated with DS, particularly the impacts of different syntenic regions on these phenotypes.

作为唐氏综合征（DS）的基因组基础，人类21三体是儿童和青少年智力残疾最常见的遗传原因。人类21号染色体（Hsa21）上的基因组区域与小鼠基因组中的三个区域存在同线性关系，这三个区域分别位于小鼠10号染色体（Mmu10）、16号染色体（Mmu16）和17号染色体（Mmu17）上。最近，我们利用染色体工程技术开发了三种新的小鼠模型，其基因型分别为Dp(10)1Yey/+、Dp(16)1Yey/+或Dp(17)1Yey/+，它们分别在Mmu10、Mmu16或Mmu17上包含一个跨越整个与Hsa21同线性区域的重复片段。在这项研究中，我们分析了这些模型的海马长时程增强（LTP）和认知行为。我们的结果表明，虽然Dp(17)1Yey/+基因型会导致海马LTP异常，但Dp(16)1Yey/+基因型会导致海马LTP异常以及学习/记忆受损。因此，这些突变小鼠可作为有力工具，用于进一步了解与DS相关的认知相关表型的潜在机制，特别是不同同线性区域对这些表型的影响。