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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.

Reversal learning paradigm reveals deficits in cognitive flexibility in the Fmr1 knockout male mouse