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. 2008 Jul;33(6):863-73.
doi: 10.1016/j.psyneuen.2008.03.011. Epub 2008 May 12.

Altered hypothalamus-pituitary-adrenal gland axis regulation in the expanded CGG-repeat mouse model for fragile X-associated tremor/ataxia syndrome

J R Brouwer  1 , E Severijnen, F H de Jong, D Hessl, R J Hagerman, B A Oostra, R Willemsen
Affiliations

Altered hypothalamus-pituitary-adrenal gland axis regulation in the expanded CGG-repeat mouse model for fragile X-associated tremor/ataxia syndrome

J R Brouwer et al. Psychoneuroendocrinology. 2008 Jul.

Abstract

The human FMR1 gene contains an unstable CGG-repeat in its 5' untranslated region. The repeat length in the normal population is polymorphic (5-54 CGG-repeats). Individuals carrying lengths beyond 200 CGGs (i.e. the full mutation) show hypermethylation and as a consequence gene silencing of the FMR1 gene. The absence of the gene product FMRP causes the fragile X syndrome, the most common inherited form of mental retardation. Elderly carriers of the premutation (PM), which is defined as a repeat length between 55 and 200 CGGs, can develop a progressive neurodegenerative syndrome: fragile X-associated tremor/ataxia syndrome (FXTAS). The high FMR1 mRNA levels observed in cells from PM carriers have led to the hypothesis that FXTAS is caused by a pathogenic RNA gain-of-function mechanism. Apart from tremor/ataxia, specific psychiatric symptoms have been described in PM carriers with or without FXTAS. Since these symptoms could arise from elevated stress hormone levels, we investigated hypothalamic-pituitary-adrenal (HPA) axis regulation using a knock-in mouse model with an expanded CGG-repeat in the PM range (>98 repeats) in the Fmr1 gene, which shows repeat instability, and displays biochemical, phenotypic and neuropathological characteristics of FXTAS. We show elevated levels of corticosterone in serum and ubiquitin-positive inclusions in both the pituitary and adrenal gland of 100-week-old animals. In addition, we demonstrate ubiquitin-positive inclusions in the amygdala from aged expanded CGG-repeat mice. We hypothesize that altered regulation of the HPA axis and the amygdala and higher stress hormone levels in the mouse model for FXTAS may explain associated psychological symptoms in humans.

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Figures

Figure 1
Figure 1
Fmrp levels at different CGG-repeat lengths in 100-week old whole mouse brain lysates. An antibody against Gapdh was used as loading control. Fmrp levels decrease mildly as CGG-repeat length increases. Quantification of the amount of Fmrp in each sample relative to wt brain revealed 100% for 112 and 129 CGG-repeats and 80% and 70% for 174 and 184 CGGs respectively.
Figure 2
Figure 2
Mean corticosterone levels as measured in CGG and wt mice at 25 and 100 weeks of age. Error bars represent 95% confidence intervals (mean ± 1.96 * st.dev). One-way ANOVA on logtransformed corticosterone levels revealed that the four groups, based on genotype and age, were significantly different (Fdf=3=10.675, p<0.001). Bonferroni corrected posthoc pairwise comparison revealed a statistically significant geometrical mean difference (GMD) between CGG and wt mice at 100 weeks (GMD=285.4 nmol/L, p=0.002) and between CGG mice at 100 weeks and CGG mice at 25 weeks (GMD=338.4 nmol/L, p<0.001).
Figure. 3
Figure. 3
Immunohistochemistry with antibodies against ubiquitin and Fmrp in pituitary gland of 100-week old CGG mice. A: Many intranuclear ubiquitin-positive inclusions (arrows) are seen in the pars intermedia, while hardly any were observed in the pars posterior. B: Ubiquitin-positive inclusions in the pars intermedia. C: Highest levels of Fmrp are observed in the pars intermedia. D: Fmrp expression in the pars intermedia. PA: pars anterior, PI: pars intermedia, PP: pars posterior
Figure 4
Figure 4
Immunohistochemistry with an antibody against ubiquitin show ubiquitin-positive inclusions in adrenal gland of 100-week old CGG mice. A: Ubiquitin-positive intranuclear inclusions (arrows) in chromaffin cells of the adrenal gland. B+C: Elongated, irregularly shaped ubiquitin-positive intranuclear inclusions in the zona fasciculata of the adrenal gland. D: Cytoplasmic inclusions (arrow heads) in the zona fasciculata of the adrenal gland.
Fig 5
Fig 5
Ubiquitin-positive intranuclear inclusions in the amygdala of a 100-week old CGG mouse. A en B show the posteromedial amygdalohippocampal nucleus, where B is a higher magnification of what is seen in A.
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