Dp(10)2Yey mouse model of Down syndrome exhibits aberrant cognition, hippocampal-prefrontal neural dynamics and cytoarchitecture

The Dp(10)2Yey mouse carries a ~2.3 Mb intra-chromosomal duplication of mouse chromosome 10 (Mmu10) that makes it an essential model for aspects of Down syndrome (DS, trisomy 21). Specifically, these animals carry extra copies of Mmu10 genes that are homologous to those on human chromosome 21 (Hsa21). Here, we report spatial memory impairment and anxiety-like behaviour in this model alongside altered neural activity in the medial prefrontal cortex (mPFC) and hippocampus (HPC). Specifically, Dp(10)2Yey DS mice showed impaired spatial alternation associated with increased ripple activity in mPFC during the period of memory consolidation, and reduced mobility in a novel environment accompanied by reduced theta-gamma phase-amplitude coupling in HPC. Finally, we found alterations in the number of interneuron subtypes in mPFC and HPC that may contribute to the observed phenotypes and highlight potential approaches to ameliorate the effects of human trisomy 21. Hippocampal cells from the Dp(10)2Yey mouse and wildtype littermates were dissociated and analysed by scRNAseqDp(10)2Yey小鼠携带一段约2.3 Mb的小鼠10号染色体（Mmu10）染色体内重复片段，使其成为研究唐氏综合征（DS，21三体）相关表型的关键模型。具体而言，该模型小鼠携带与人类21号染色体（Hsa21）上基因同源的Mmu10基因额外拷贝。本研究报道了该模型小鼠的空间记忆损伤与类焦虑行为，同时伴随内侧前额叶皮层（mPFC）与海马体（HPC）的神经活动异常。具体表现为：Dp(10)2Yey唐氏综合征小鼠在记忆巩固阶段出现空间交替任务受损，同时伴随mPFC内锐波活动增强；在新环境中活动能力降低，同时HPC内θ-γ相位振幅耦合减弱。最后，我们发现mPFC与HPC内中间神经元亚型的数量改变可能是上述观测表型的成因，并为改善人类21三体的相关症状提供了潜在干预方向。本研究还对Dp(10)2Yey小鼠及其野生型同窝仔鼠的海马体细胞进行了解离，并通过单细胞RNA测序（scRNAseq）开展分析。