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Updated: Oct 16, 2025
Trace Fear Conditioning in Mice
Published on: March 20, 2014
Context Fear Conditioning in Down Syndrome Mouse Models: Effects of Trisomic Gene Content, Age, Sex and Genetic
Md Mahiuddin Ahmed1,2, Aaron Block2, Nicolas Busquet3
1Department of Neurology, Linda Crnic Institute for Down Syndrome, University of Colorado Alzheimer's and Cognition Center, Aurora, CO 80045, USA.
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.
Insights
Preclinical studies for Down syndrome (DS) intellectual disability (ID) treatments require diverse mouse models. Evaluating context fear conditioning (CFC) reveals that genotype, sex, age, and genetic background significantly impact results.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Down syndrome (DS), caused by trisomy of human chromosome 21 (Hsa21), is the leading genetic cause of intellectual disability (ID).
- Currently, no effective pharmacotherapies exist for DS-associated ID.
- Reliable preclinical models are crucial for developing and testing potential ID treatments.
Purpose of the Study:
- To assess the impact of genetic background, sex, and age on learning and memory in mouse models of Down syndrome.
- To identify limitations in standard preclinical evaluations for ID in DS.
Main Methods:
- Context fear conditioning (CFC) was used to evaluate learning and memory.
- Three mouse models trisomic for different sets of Hsa21 orthologs (Dp16, Dp17, Dp10) were studied.
- Mice were examined at different ages (3 and 18 months) and on varied genetic backgrounds (C57BL/6J and DBA/2J hybrids).
Main Results:
- Performance in CFC was significantly influenced by genotype, sex, age, and genetic background.
- Dp16, Dp17, and Dp10 mouse models exhibited varying responses in fear conditioning.
- Hybrid mice showed different learning and memory profiles compared to those on a standard background.
Conclusions:
- Preclinical evaluations for DS ID require careful consideration of multiple factors, including mouse model genetics, sex, age, and background.
- Utilizing diverse mouse models and testing conditions will enhance the reliability of drug efficacy studies for ID in DS.
- These findings underscore the need for comprehensive preclinical strategies to accelerate the development of effective pharmacotherapies for Down syndrome.
