Unaltered hormonal response to stress in a mouse model of fragile X syndrome

Abstract

SummaryReports in the clinical literature and studies of fmr-1 knockout mice have led to the hypothesis that, in addition to mental retardation, fragile X syndrome is characterized by a dysregulation of hypothalamic-pituitary-adrenal axis function. We have systematically examined this hypothesis by studying the effects of stress on adrenocorticotrophic hormone and corticosterone levels in adult, male fmr1 knockout mice. Initially we determined the circadian rhythms of the plasma hormone levels in both wild type and fmr1 knockout mice and established the optimal time to impose the stress. We found no genotypic differences in the circadian rhythms of either hormone. We studied two types of stressors, immobilization and spatial novelty; spatial novelty was 5 min in an elevated plus-maze. We varied the duration of immobilization and followed the time course of recovery of hormones to their pre-stress levels. Despite the lower anxiety exhibited by fmr-1 knockout mice in the elevated plus maze, hormonal responses to and recovery from this spatial novelty were similar in both genotypes. Further, we found no genotypic differences in hormonal responses to immobilization stress. The results of our study indicate that, in FVB/NJ mice, the hormonal response to and recovery from acute stress is unaltered by the lack of fragile X mental retardation protein.

Hypothalamic-pituitary-adrenal axis function in Fragile X Syndrome and its relationship to behaviour: A systematic review

“…however Qin and Smith (2008) did not find any genotype differences after the same stressor when using FVB/NJ male mice. However, clearly, there may have been other methodological differences between the studies which caused the differences in the results (see Table 1 for summary of key study methodology).…”

“…As ; Ghilan et al, 2015). Furthermore, in a more detailed analysis, Qin and Smith (2008) assessed the baseline circadian rhythm of both genotypes and found no difference at any of the six time-points tested (Qin & Smith, 2008). However, two studies did identify genotype differences, though the nature of the difference contrasted: de Diego-Otero and colleagues (2009) found that KO mice had lower corticosterone levels at baseline than WT controls; in contrast, Qin and colleagues (2011) found a main effect whereby KO mice generally had higher corticosterone than WT controls.…”

“…The majority of studies found no genotype effect in their comparisons at single time-points, with male animals (Markham et al, 2006;Lauterborn, 2004;Nielsen et al, 2009;Eadie et al, 2009;Ghilan et al, 2015). Furthermore, in a more detailed analysis, Qin and Smith (2008) assessed the baseline circadian rhythm of both genotypes and found no difference at any of the six time-points tested (Qin & Smith, 2008 is no evidence to suggest baseline HPA activity is altered in males with FXS, based on the preclinical evidence.…”

“…One study was identified which included female mice (Markham et al, 2006; gender comparisons summarised in Table 4 (Qin et al, 2011;de Diego-Otero et al, 2008;Qin & Smith, 2008;Eadie et al, 2009). No research has been conducted to identify which mouse behaviours correspond to clinically significant behaviours in FXS.…”

“…Seven studies were identified which had compared the magnitude of responses of male KO and WT mice to this procedure (implemented for between 15 minutes and three hours; three studies did not observe any genotype difference in the magnitude of corticosterone responses to restraint stress (Markham et al, 2006;Nielsen et al, 2009;Qin & Smith, 2008) and a further four studies also observed no difference using other acute stress paradigms, including exposure to spatial novelty (Nielsen et al, 2009;Qin & Smith, 2008;Qin et al, 2011) and swim stress (Nielsen et al, 2009). …”