Fragile X syndrome is a genetic disease, which is primarily characterized by cognitive impairments in learning and memory. The syndrome tends to affect males more than females, but the symptoms are similar in both (with the added risk of infertility in females and the development of macroorchidism – overgrown testes – in males).
Normally, individuals have about 30 CGG repeats of the FMR1 gene. However, when and if the number of repeats greatly exceeds the average 30 (i.e. 50-200 CGG repeats), degenerative and developmental disorders result. Once the repeats exceed 200 in number, the entire gene is functionally turned off (via a gene silencing process known as methylation) at which point, Fragile X syndrome sets in.
In order to study some of the basic molecular and behavioral underpinnings of Fragile X syndrome, researchers developed a mouse model with the FMR1 gene knocked out – a “FMR1 KO mouse”. The targeted deletion of the FMR gene prevents the expression of the resulting FMR protein, or FMRP and allows for the careful study of its effect on learning and memory.
While this mouse is important in understanding some of the behavioral and molecular consequences of this genetic deletion, it is important to note that these mice cannot be considered “mice with Fragile X”. Rather, these mice mimic many of the same symptoms and phenotypic issues we see in humans with the disease. As such, they are useful model organisms and can be tested in a variety of behavioral tests that may challenge some of the core issues seen in those with Fragile X: learning, memory and in some cases, anxiety and infertility.
Performance in Behavioral Tasks
While the FMR1 KO mice definitely have some issues in behavioral task performance, they are not abnormal in all behavioral tasks. Here’s a summary of their performance on various maze-based tasks, to date:
Elevated plus maze: In a study by Crusio et al., there was no noted difference in performance between FMR1 KO mice and control mice in the EPM, suggesting no difference in anxiety (at least in this test) between the two groups.
Motor Activity Test : In a test of motor activity, FMR1 KO mice showed significantly greater number of crossings through infrared beams (in an empty cage) and greater activity overall, suggesting that these mice are more hyperactive than their control littermates.
Open field test: Consistent with the above finding, FMR1 KO mice showed greater levels of locomotion in the OFT, compared to their littermate control mice. In fact, in other studies and tests, hyperactivity is noted as a behavioral outcome of these transgenic mice.
Exploratory Behavior Test: While the difference in time spent in the lit compartment was not statistically significant between mutant mice and control littermates, the KO mice displayed greater line crossings than their control littermates. This told researchers that the KO mice demonstrate greater exploratory behavior than their littermate control mice. Given the OFT data above, it is possible that this exploratory behavior is linked to their baseline hyperactivity.
Radial maze: Although this is fundamentally test of spatial learning, it also reveals differences in exploratory behavior. FMR1 KO mice made more mistakes and fewer entries into the target arm than their littermate controls, overall. The researchers in this study hypothesized that the increase in exploratory behavior could either be interpreted as an inability to learn (and thus needing to recheck a given arm several times) or it could simply be the result of hyperactivity.
Morris Water Maze: As another test of spatial memory, the Morris Water Maze (MWM) taps into a rodent’s ability to remember the hidden target platform by using spatial cues and memory to navigate. Interestingly, the KO mice performed normally in this task and were able to learn but, notably, the rate of learning was much slower than their control littermates. Also, in reversal trials (where the target platform is moved to a new location), KO mice are slower learners than their control littermates.
Overall, the FMR1 KO mouse serves as a useful mouse model for studying the behavioral and molecular abnormalities that are associated with Fragile X. They are also useful for the study of neurodevelopmental disorders that share similar cognitive impairments (for example, they have recently been used in the study of autism). These mice can be purchased from Jackson Laboratories either on a hybrid background strain here or a c57bl/6 background strain.
References
THEDUTCHBELGIANFRAGILEXCONSOR, . (1994). Fmr1 knockout mice: A model to study fragile X mental retardation Cell, 78 (1) DOI: 10.1016/0092-8674(94)90569-X
Mineur YS, Sluyter F, de Wit S, Oostra BA, & Crusio WE (2002). Behavioral and neuroanatomical characterization of the Fmr1 knockout mouse. Hippocampus, 12 (1), 39-46 PMID: 11918286
Naviaux JC, Wang L, Li K, Bright AT, Alaynick WA, Williams KR, Powell SB, & Naviaux RK (2015). Antipurinergic therapy corrects the autism-like features in the Fragile X (Fmr1 knockout) mouse model. Molecular autism, 6 PMID: 25705365