Male and female Fmr1 knockout mice on C57 albino background exhibit spatial learning and memory impairments

Abstract

Impaired spatial learning is a prominent deficit in fragile X syndrome (FXS). Previous studies using the Fmr1 knockout (KO) mouse model of FXS have not consistently reported a deficit in spatial learning. Fmr1 KO mice bred onto an albino C57BL/6J-Tyr c-Brd background showed significant deficits in several primary measures of performance during place navigation and probe trials in the Morris water maze. Fmr1 KO mice were also impaired during a serial reversal version of the water maze task. We examined fear conditioning as an additional cognitive screen. Knockout mice exhibited contextual memory deficits when trained with unsignaled shocks; however, deficits were not found in a separate group of KO mice trained with signaled shocks. No potentially confounding genotypic differences in locomotor activity were observed. A decreased anxiety-like profile was apparent in the open field, as others have noted, and also in the platform test. Also as previously reported, startle reactivity to loud auditory stimuli was decreased, prepulse inhibition and social interaction increased in KO mice. Female Fmr1 KO mice were tested along with male KO mice in all assays, except for social interaction. The female and male KO exhibited very similar impairments indicating that sex does not generally drive the behavioral symptoms of the disorder. Our results suggest that procedural factors, such as the use of albino mice, may help to reliably detect spatial learning and memory impairments in both sexes of Fmr1 KO mice, making it more useful for understanding FXS and a platform for evaluating potential therapeutics.

Modeling fragile X syndrome in the <i>Fmr1</i> knockout mouse

“…These acquisition deficits have been replicated (106), but not consistently (75,174). Similarly, deficits in reversal learning in Fmr1 KO mice were replicated in some studies (106,193), but not all (75). Based on the variable results across laboratories, the spatial learning deficits identified in earlier studies may require very specific conditions in order to reproduce these results.…”

“…In the majority of published studies, however, probe trial analyses revealed no differences between Fmr1 KO and wildtype mice, indicating limited and selective deficits in spatial learning and memory (48,75,174,192,193). However, some probe trial differences have been observed in Fmr1 KO mice (106). Some researchers have observed task-specific impairments in spatial cognition rather than global impairments (183,184), although global cognitive impairments in individuals with FXS have also been reported (160-162).…”

“…Trace-cued fear conditioning requires hippocampus and prefrontal cortex (177,178) and may or may not be independent of the amygdala (179,180). Trace fear conditioning, a more difficult task in which the tone and shock are not simultaneous during training, indicated that Fmr1 KO mice may have deficits (74) but others showed that Fmr1 KO mice appeared equal or superior to wildtype mice in the acquisition of trace fear conditioning (106).…”

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

“…In complete darkness, FMRP was found to regulate the length of circadian period (Zhang et al 2008) since shorter activity periods of wheel running were observed in the Fmr1 KO mice compared with controls. Interestingly, FMRP affects circadian rhythmicity differently in females and males since ambulatory activity during the light phase was enhanced only in the Fmr1 KO females (Baker et al 2010) and no changes were reported in males.…”

“…In this task a weak stimulus, such as a tone, inhibits the subsequent response to a stronger, louder stimulus, if presented within 100 msec (Nielsen et al 2002). Presently, how the Fmr1 KO mouse processes incoming information is still unclear, because either no differences (Peier et al 2000;Yan et al 2004;Spencer et al 2006;Thomas et al 2012) or enhanced startle responses were shown (Chen and Toth 2001;Nielsen et al 2002;Frankland et al 2004;de Vrij et al 2008;Baker et al 2010;Olmos-Serrano et al 2011;Veeraragavan et al 2012) compared with control animals. However, in one study (Frankland et al 2004), Fmr1 KO mice showed an excessive reaction to auditory stimuli, similar to humans (Renoux et al 2014).…”