Dissecting the contribution of human chromosome 21 syntenic regions to recognition memory processes in adult and aged mouse models of Down syndrome

Tara Canonica; Emma J Kidd; Dorota Gibbins; Eva Lana-Elola; Elizabeth M C Fisher; Victor L J Tybulewicz; Mark Good

doi:10.3389/fnbeh.2024.1428146

Dissecting the contribution of human chromosome 21 syntenic regions to recognition memory processes in adult and aged mouse models of Down syndrome

Front Behav Neurosci. 2024 Jul 10:18:1428146. doi: 10.3389/fnbeh.2024.1428146. eCollection 2024.

Authors

Tara Canonica¹, Emma J Kidd², Dorota Gibbins³, Eva Lana-Elola³, Elizabeth M C Fisher⁴, Victor L J Tybulewicz³, Mark Good¹

Affiliations

¹ School of Psychology, Cardiff University, Cardiff, United Kingdom.
² School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom.
³ Francis Crick Institute, London, United Kingdom.
⁴ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom.

Abstract

Background: 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.

Hypothesis: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: aging; down syndrome; glutamate receptors; hippocampus; mouse models; object tasks; recognition memory.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Wellcome Trust (grants 098327 and 098328 to VT and EF) and the Francis Crick Institute (CC 2080 to VT) that received its core funding from Cancer Research UK (CC 2080), the UK Medical Research Council (CC 2080), and the Wellcome Trust (CC 2080). Publication costs were provided by Cardiff University.