■人类21号染色体的三体(Hsa21)导致一系列称为唐氏综合症(DS)的特征,智力障碍最常见的遗传形式。Hsa21与小鼠染色体16(Mmu16)上的小鼠基因组中的三个区域直系同源,Mmu17和Mmu10。我们通过评估这三个区域对记忆功能和年龄依赖性认知功能下降的贡献来研究基因型-表型关系。使用三种DS小鼠模型,Dp1Tyb,Dp(17)3Yey,Dp(10)2Yey,分别在Mmu16,Mmu17和Mmu10上携带Hsa21直系同源物的额外副本。
■关于DS小鼠模型中认知功能的先前研究主要集中在具有Mmu16区域额外拷贝的模型上,而关于拷贝数增加对Mmu17和Mmu10对认知的影响以及这如何与衰老的影响相互作用的知识相对较少。由于衰老是DS的认知和精神病学变化的关键因素,我们假设衰老会对Dp1Tyb的记忆功能产生不同的影响,Dp(17)3Yey,和Dp(10)2Yey,DS的模型。
■Young(12-13个月大(18-20个月的小鼠Dp1Tyb,Dp(17)3Yey和Dp(10)2Yey小鼠在一系列对象识别记忆测试中进行了测试,该测试评估了对象的新颖性检测,新颖的位置检测和关联对象就地记忆。在行为测试之后,使用标准免疫印迹技术分析海马和额叶皮质组织中谷氨酸能受体蛋白的表达。
■Young(12-13个月大(18-20个月的小鼠Dp1Tyb,Dp(17)3Yey和Dp(10)2Yey小鼠在一系列对象识别记忆测试中进行了测试,该测试评估了对象的新颖性检测,新颖的位置检测和关联对象就地记忆。在行为测试之后,使用标准免疫印迹技术分析海马和额叶皮质组织中谷氨酸能受体蛋白的表达。
■我们的结果表明,在DS小鼠模型中,不同的Hsa21直系同源区域对认知功能障碍有不同的贡献,并且衰老与Mmu10上Hsa21直系同源基因的三重重复相互作用。
UNASSIGNED: Trisomy of human chromosome 21 (Hsa21) results in a constellation of features known as Down syndrome (DS), the most common genetic form of intellectual disability. Hsa21 is orthologous to three regions in the mouse genome on mouse chromosome 16 (Mmu16), Mmu17 and Mmu10. We investigated genotype-phenotype relationships by assessing the contribution of these three regions to memory function and age-dependent cognitive decline, using three mouse models of DS, Dp1Tyb, Dp(17)3Yey, Dp(10)2Yey, that carry an extra copy of the Hsa21-orthologues on Mmu16, Mmu17 and Mmu10, respectively.
UNASSIGNED: Prior research on cognitive function in DS mouse models has largely focused on models with an extra copy of the Mmu16 region and relatively little is known about the effects of increased copy number on Mmu17 and Mmu10 on cognition and how this interacts with the effects of aging. As aging is is a critical contributor to cognitive and psychiatric changes in DS, we hypothesised that ageing would differentially impact memory function in Dp1Tyb, Dp(17)3Yey, and Dp(10)2Yey, models of DS.
UNASSIGNED: Young (12-13 months and old (18-20 months mice Dp1Tyb, Dp(17)3Yey and Dp(10)2Yey mice were tested on a battery of object recognition memory test that assessed object novelty detection, novel location detection and associative object-in place memory. Following behavioral testing, hippocampal and frontal cortical tissue was analysed for expression of glutamatergic receptor proteins using standard immunoblot techniques.
UNASSIGNED: Young (12-13 months and old (18-20 months mice Dp1Tyb, Dp(17)3Yey and Dp(10)2Yey mice were tested on a battery of object recognition memory test that assessed object novelty detection, novel location detection and associative object-in place memory. Following behavioral testing, hippocampal and frontal cortical tissue was analysed for expression of glutamatergic receptor proteins using standard immunoblot techniques.
UNASSIGNED: Our results show that distinct Hsa21-orthologous regions contribute differentially to cognitive dysfunction in DS mouse models and that aging interacts with triplication of Hsa21-orthologous genes on Mmu10.