Abstract
Background: Loss of FMR1 is associated with Fragile X syndrome, amongst the most prevalent inherited intellectual disability. Despite extensive research in this area, previous studies have failed to detect consistent evidence of cognitive impairments in the Morris water maze (MWM) task in the Fmr1 knockout (KO) mouse. However, few studies have examined cognitive flexibility in a reversal form of the MWM task, which may illuminate subtle learning deficits. Methods: Adult male Fmr1 wildtype (WT) and KO mice were bred and tested in the MWM reversal paradigm. The testing paradigm consisted of two blocks per day, with 4 trials per block to locate a hidden platform. After the last trials on the fourth day of testing, the animals were given a probe trial with the platform removed. The following week, the location of the platform was switched to the opposite quadrant and the animals received 2 more days of testing, with 4 blocks in total. Results: As expected, Fmr1 KO mice did not display a learning deficit during the acquisition phase, F genotype (1, 24) = 0.034, p = 0.854, and performed similarly on the probe trial, F genotype (1, 23) = 0.024, p = 0.877. However, during the reversal phase of learning, Fmr1 KO mice showed deficits in their ability to learn the new location of the platform, F genotype (1, 23) = 3.93, p = 0.059. Further independent samples t-testing revealed that KO animals displayed significantly higher latency to reach the hidden platform during the third trial, t(23) = -2.96, p < 0.01. Conclusions: While previous studies have not demonstrated deficits in spatial memory in the Fmr1 KO model, it is possible that the acquisition phase of the task is less sensitive to deficits in learning. Future studies using this model to evaluate therapeutic interventions should consider utilizing the MWM reversal paradigm.
Highlights
Fragile X syndrome (FXS) is a neurodevelopmental disorder, caused by a trinucleotide expansion mutation in the FMR1 gene, and is one of the most prevalent inherited forms of intellectual disability[1]
Animals Male Fmr1+/+ and female Fmr1+/- FVB.129P2-Pde6b+Tyrc-ch Fmr1tm1Cgr/J (Stock No: 004624, The Jackson Laboratory, Bar Harbor, ME, USA) mice were used as breeders (9 total breeding pairs) to produce the following groups: male WT and male KO pups
In support of our findings, deficits in long-term potentiation in the prefrontal cortex have been demonstrated in the Fmr[1] KO mouse, the area on which the ability to adapt to a new location in this task is dependent on 11–13
Summary
Fragile X syndrome (FXS) is a neurodevelopmental disorder, caused by a trinucleotide expansion mutation in the FMR1 gene, and is one of the most prevalent inherited forms of intellectual disability[1]. Despite extensive research in this area, previous studies have failed to detect consistent evidence of cognitive impairments in the Morris water maze (MWM) task in the Fmr[1] knockout (KO) mouse. Few studies have examined cognitive flexibility in a reversal form of the MWM task, which may illuminate subtle learning deficits. Conclusions: While previous studies have not demonstrated deficits in spatial memory in the Fmr[1] KO model, it is possible that the acquisition phase of the task is less sensitive to deficits in learning. Future studies using this model to evaluate therapeutic interventions should consider utilizing the MWM reversal paradigm
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