Cognitive impairments in a Down syndrome model with abnormal hippocampal and prefrontal dynamics and cytoarchitecture
Phillip M. Muza,
Daniel Bush,
Marta Pérez-González,
Ines Zouhair,
Karen Cleverley,
Miriam L. Sopena,
Rifdat Aoidi,
Steven J. West,
Mark Good,
Victor L.J. Tybulewicz,
Matthew C. Walker,
Elizabeth M.C. Fisher,
Pishan Chang
Affiliations
Phillip M. Muza
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK
Daniel Bush
Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK; UCL Institute of Cognitive Neuroscience and UCL Queen Square Institute of Neurology, University College London, London WC1N 3AZ, UK
Marta Pérez-González
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK
Ines Zouhair
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK
Karen Cleverley
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK
Miriam L. Sopena
Bioinformatics and Biostatistics, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
Rifdat Aoidi
Immune Cell Biology and Down Syndrome Laboratory, The Francis Crick Institute, London NW1 1AT, UK
Steven J. West
Sainsbury Wellcome Centre, University College London, London W1T 4JG, UK
Mark Good
School of Psychology, Cardiff University, Cardiff CF10 3AT, UK
Victor L.J. Tybulewicz
Immune Cell Biology and Down Syndrome Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Corresponding author
Matthew C. Walker
Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK; Corresponding author
Elizabeth M.C. Fisher
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK; Corresponding author
Pishan Chang
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK; School of Physiology, Pharmacology, and Neuroscience, University of Bristol, Bristol BS8 1TD, UK; Corresponding author
Summary: The Dp(10)2Yey mouse carries a ∼2.3-Mb intra-chromosomal duplication of mouse chromosome 10 (Mmu10) that has homology to human chromosome 21, making it an essential model for aspects of Down syndrome (DS, trisomy 21). In this study, we investigated neuronal dysfunction in the Dp(10)2Yey mouse and report spatial memory impairment and anxiety-like behavior alongside altered neural activity in the medial prefrontal cortex (mPFC) and hippocampus (HPC). Specifically, Dp(10)2Yey mice showed impaired spatial alternation associated with increased sharp-wave ripple activity in mPFC during a 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.
