Context Fear Conditioning in Down Syndrome Mouse Models: Effects of Trisomic Gene Content, Age, Sex and Genetic Background.

Md Mahiuddin Ahmed,Aaron Block,Nicolas Busquet,Katheleen J Gardiner

doi:10.3390/genes12101528

Md Mahiuddin Ahmed, Aaron Block + Show 2 more

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https://doi.org/10.3390/genes12101528

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Journal: Genes	Publication Date: Sep 28, 2021
Citations: 3	License type: CC BY 4.0

Affiliation: University of Colorado Anschutz Medical Campus

Abstract

Down syndrome (DS), trisomy of the long arm of human chromosome 21 (Hsa21), is the most common genetic cause of intellectual disability (ID). Currently, there are no effective pharmacotherapies. The success of clinical trials to improve cognition depends in part on the design of preclinical evaluations in mouse models. To broaden understanding of the common limitations of experiments in learning and memory, we report performance in context fear conditioning (CFC) in three mouse models of DS, the Dp(16)1Yey, Dp(17)1Yey and Dp(10)1Yey (abbreviated Dp16, Dp17 and Dp10), separately trisomic for the human Hsa21 orthologs mapping to mouse chromosomes 16, 17 and 10, respectively. We examined female and male mice of the three lines on the standard C57BL/6J background at 3 months of age and Dp17 and Dp10 at 18 months of age. We also examined female and male mice of Dp17 and Dp10 at 3 months of age as F1 hybrids obtained from a cross with the DBA/2J background. Results indicate that genotype, sex, age and genetic background affect CFC performance. These data support the need to use both female and male mice, trisomy of sets of all Hsa21 orthologs, and additional ages and genetic backgrounds to improve the reliability of preclinical evaluations of drugs for ID in DS.

Highlights

Down syndrome (DS) is caused by an extra copy of all or, rarely, part of the long arm of human chromosome 21 (Hsa21)
We found that aspects of context fear conditioning (CFC) performance are influenced by specific trisomy, sex, age and genetic background
Mice of each sex and genotype were separated into two groups: shock-context (SC), in which mice received the shock in the training session immediately upon being placed in the novel cage, and context-shock (CS), in which mice received the shock in the training session three minutes after being placed in the novel cage

Summary

Introduction

Down syndrome (DS) is caused by an extra copy of all or, rarely, part of the long arm of human chromosome 21 (Hsa). Over the last several years, interest has grown in conducting clinical trials with pharmacotherapies to lessen or prevent ID in DS [12,13]. None produced significant, practical, positive outcomes for participants (ClinicalTrials.gov: NCT01576705, NCT02304302, NCT02024789, NCT02484703; [14,15]). Many reasons for these failures can be considered, including number and age of the participants and duration of the trial. Another consideration is that, prior to clinical trials, candidate drugs most commonly are first evaluated in mice. As with other human diseases, the experimental design of such preclincal evaluations influences their reliability in prediction of outcomes for patients (reviewed in [16])

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