Normal Performance of Fmr1 Mice on a Touchscreen Delayed Nonmatching to Position Working Memory Task
Open accessAbstract
Fragile X syndrome is a neurodevelopmental disorder characterized by mild-to-severe cognitive deficits. The complete absence of Fmr1 and its protein product in the mouse model of fragile X (Fmr1 KO) provides construct validity. A major conundrum in the field is the remarkably normal performance of Fmr1 mice on cognitive tests in most reports. One explanation may be insufficiently challenging cognitive testing procedures. Here we developed a delayed nonmatching to position touchscreen task to test the hypothesis that paradigms placing demands on working memory would reveal robust and replicable cognitive deficits in the Fmr1 KO mouse. We first tested Fmr1 KO mice (Fmr1) and their wild-type (WT) littermates in a simple visual discrimination task, followed by assessment of reversal learning. We then tested Fmr1 and WT mice in a new touchscreen nonmatch to position task and subsequently challenged their working memory abilities by adding delays, representing a higher cognitive load. The performance by Fmr1 KO mice was equal to WTs on both touchscreen tasks. Last, we replicated previous reports of normal performance by Fmr1 mice on Morris water maze spatial navigation and reversal. These results indicate that, while the Fmr1 mouse model effectively recapitulates many molecular and cellular aspects of fragile X syndrome, the cognitive profile of Fmr1 mice generally does not recapitulate the primary cognitive deficits in the human syndrome, even when diverse and challenging tasks are imposed.
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Standard learning and memory tasks detect cognitive deficits in Fmr1-knockout mice in some reports but normal performance in others, within and across laboratories, independent of genetic background.
“Standard learning and memory tasks for mice — including the Morris water maze, fear conditioning, passive avoidance, novel object recognition, visual discrimination and delayed non-matching to position — detected deficits in Fmr1-KO mice in some reports, but normal performance in others, both within and across laboratories and unrelated to the genetic background (FVB/NJ, FVB/AntJ or C57BL/6J)61–63”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [63]
Available mouse operant touchscreen paradigms seem to have face validity relative to human cognitive touchscreen tasks, although there is concern that the cognitive profile of Fmr1-KO mice may not emulate the cognitive deficits in the human syndrome.
“available mouse operant touchscreen paradigms seem to have face validity63,89,101–104 relative to human cognitive touchscreen tasks97, although there is concern that the cognitive profile of Fmr1-KO mice may not emulate the cognitive deficits in the human syndrome63.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [63]
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Self-citation
- Authors
- Leach, P. T., Hayes, J., Pride, M., Silverman, J. L., & Crawley, J. N.
- Affiliations
- University of California, Davis (US)
- Corresponding author
- Leach, Prescott T.
- Venue
- eneuro
- Publisher
- Society for Neuroscience
- Published
- 2016-01
- Volume
- 3
- Issue
- 1
- Pages
- ENEURO.0143-15.2016
- ISSN
- 2373-2822 (ISSN-L)
- PMC
- PMC4800045
- OpenAlex
- W2299305793
- Cited by
- 27
- References
- 82
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 5 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 3 · 2018: 4 · 2017: 5 · 2016: 1
- FWCI
- 3.50
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- eNeuro (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (1R01-NS-085709, R01NS085709)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD079125)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Developmental Neuroscience › Williams Syndrome Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- fragile X syndrome, Fmr1 knockout mice, working memory, touchscreen task, reversal learning, Morris water maze, spatial navigation, cognitive impairment, construct validity, cognitive load
- MeSH terms
- Animals, Choice Behavior, Discrimination, Psychological, Disease Models, Animal, Female, Fragile X Syndrome, Male, Memory, Short-Term, Mice, Inbred C57BL, Reversal Learning, Mice, Knockout, Maze Learning, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1
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