Abstract
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.
Highlights
Fragile X syndrome (FXS) is a genetic disorder caused by a hypermethylated FMR1 gene, which reduces expression of fragile X mental retardation protein (FMRP; Sutcliffe et al, 1992; Feng et al, 1995)
The number of days to reach criterion for acquisition did not differ between Fmr1 and WT mice (Fig. 2C)
The present studies attempted to challenge the cognitive capabilities of Fmr1 mice by implementing the following four touchscreen tasks: visual discrimination, reversal of the visual discrimination, nonmatching to position, and delay-dependent nonmatching to position
Summary
Fragile X syndrome (FXS) is a genetic disorder caused by a hypermethylated FMR1 gene, which reduces expression of fragile X mental retardation protein (FMRP; Sutcliffe et al, 1992; Feng et al, 1995). To understand the biological consequences of the absence of FMRP, The Dutch-Belgian Fragile X Consortium (1994) generated the Fmr knock-out (KO) mouse (Fmr1) in 1994. This genetic mouse model of FXS has been extensively used to investigate the functional outcomes of loss of Fmr. Cognitive deficits in Fmr mice have proven remarkably mild and somewhat inconsistent across publications (Kooy, 2003). Given the primary symptom of intellectual disability in humans with FXS, cognitive deficits in Fmr KO mice were expected to be robust enough to withstand some variability in methods, background genetics, and environmental issues. It is important to know whether the results from the Fmr mouse are informative for the development of treatments for FXS or whether other models would allow greater predictive validity
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