Integrative Pharmacology and Systems Neuroscience, Hospital del Mar Medical Research Institute, Barcelona Biomedical Research Park, 08003 Barcelona, Spain.
Cellular and Systems Neurobiology Laboratory, Center for Genomic Regulation, The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain.
Proc Natl Acad Sci U S A. 2020 May 26;117(21):11788-11798. doi: 10.1073/pnas.1921314117. Epub 2020 May 11.
Down syndrome (DS) is the most common form of intellectual disability. The cognitive alterations in DS are thought to depend on brain regions critical for learning and memory such as the prefrontal cortex (PFC) and the hippocampus (HPC). Neuroimaging studies suggest that increased brain connectivity correlates with lower intelligence quotients (IQ) in individuals with DS; however, its contribution to cognitive impairment is unresolved. We recorded neural activity in the PFC and HPC of the trisomic Ts65Dn mouse model of DS during quiet wakefulness, natural sleep, and the performance of a memory test. During rest, trisomic mice showed increased theta oscillations and cross-frequency coupling in the PFC and HPC while prefrontal-hippocampal synchronization was strengthened, suggesting hypersynchronous local and cross-regional processing. During sleep, slow waves were reduced, and gamma oscillations amplified in Ts65Dn mice, likely reflecting prolonged light sleep. Moreover, hippocampal sharp-wave ripples were disrupted, which may have further contributed to deficient memory consolidation. Memory performance in euploid mice correlated strongly with functional connectivity measures that indicated a hippocampal control over memory acquisition and retrieval at theta and gamma frequencies, respectively. By contrast, trisomic mice exhibited poor memory abilities and disordered prefrontal-hippocampal functional connectivity. Memory performance and key neurophysiological alterations were rescued after 1 month of chronic administration of a green tea extract containing epigallocatequin-3-gallate (EGCG), which improves executive function in young adults with DS and Ts65Dn mice. Our findings suggest that abnormal prefrontal-hippocampal circuit dynamics are candidate neural mechanisms for memory impairment in DS.
唐氏综合征（DS）是最常见的智力障碍形式。DS 的认知改变被认为依赖于学习和记忆的关键脑区，如前额叶皮层（PFC）和海马体（HPC）。神经影像学研究表明，DS 个体的脑连接增加与智商（IQ）降低相关；然而，其对认知障碍的贡献仍未解决。我们在安静清醒、自然睡眠和记忆测试期间记录了三倍体 Ts65Dn 唐氏综合征小鼠模型的 PFC 和 HPC 中的神经活动。在休息时，三倍体小鼠表现出 PFC 和 HPC 中θ振荡和跨频耦合增加，而前额叶-海马同步增强，表明局部和跨区域处理过度同步。在睡眠期间，慢波减少，γ振荡在 Ts65Dn 小鼠中放大，可能反映出轻度睡眠延长。此外，海马体中的尖波涟漪被打乱，这可能进一步导致记忆巩固不足。正常体小鼠的记忆表现与功能连接测量密切相关，表明海马体分别在θ和γ频率上控制记忆的获取和检索。相比之下，三倍体小鼠表现出较差的记忆能力和紊乱的前额叶-海马功能连接。经过 1 个月的绿茶提取物（含表没食子儿茶素没食子酸酯）慢性给药后，记忆表现和关键神经生理改变得到挽救，该提取物可改善年轻 DS 个体和 Ts65Dn 小鼠的执行功能。我们的研究结果表明，异常的前额叶-海马回路动力学是 DS 记忆障碍的候选神经机制。
