A mouse model of the fragile X premutation: Effects on behavior, dendrite morphology, and regional rates of cerebral protein synthesis

Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Neurobiology of Disease (Impact Factor: 5.08). 04/2011; 42(1):85-98. DOI: 10.1016/j.nbd.2011.01.008
Source: PubMed


Carriers of FMR1 premutation alleles have 55-200 CGG repeats in the 5' untranslated region of the gene. These individuals are at risk for fragile X associated primary ovarian insufficiency (females) and, in late life, fragile X associated tremor and ataxia syndrome (males, and to a lesser extent, females). Premutation carrier status can also be associated with autism spectrum disorder, attention deficit hyperactivity disorder, and some cognitive deficits. In premutation carriers, FMR1 mRNA levels are often higher than those with normal sized alleles. In contrast, in subjects with full mutation alleles, (>200 repeats) the FMR1 gene is silenced and FMR1 mRNA and its product, FMRP, are absent. We have studied a male knock-in (KI) mouse model of the fragile X premutation (120-140 repeats) during young adulthood. In comparison to wild type, KI mice were hyperactive, exhibited less anxiety in both the open field and the elevated zero maze, were impaired on the passive avoidance test, and showed some subtle deficits on a test of social interaction. Motor learning as assessed by the rotarod test was normal. Dendritic arbors were less complex and spine densities and lengths increased in medial prefrontal cortex, basal lateral amygdala, and hippocampus compared with wild type. Regional rates of cerebral protein synthesis measured in vivo in KI mice were increased. KI mice also had elevated levels of Fmr1 mRNA and decreased levels of FMRP. Our results highlight similarities in phenotype between KI and Fmr1 knockout mice and suggest that the decreased concentration of FMRP contributes to the phenotype in young adult KI mice.

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Available from: Gloria E Hoffman, Oct 05, 2015
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    • "Conditions were optimized to minimize DAB reactivity in Fmr1 KO tissue. We reliably observed reduced FMRP levels in CGG KI mice both by western analysis and immunohistochemistry, consistent with previous reports (Tassone et al., 2000a; Kenneson et al., 2001; Entezam et al., 2007; Qin et al., 2011; Iliff et al., 2013; Ludwig et al., 2014; Pretto et al., 2014; Figure 1). In an effort to probe a potential role of altered FMRP expression in AD pathogenesis, we evaluated FMRP in a double transgenic model of AD which contains an additional copy of the human APP gene carrying the familial Swedish (K670N/M671L) missense mutation (Haass et al., 1995), and a deletion of exon 9 in the presenilin1 gene (Prihar et al., 1999). "
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    ABSTRACT: The FMR1 protein product, FMRP, is an mRNA binding protein associated with translational inhibition of target transcripts. One FMRP target is the amyloid precursor protein (APP) mRNA, and APP levels are elevated in Fmr1 KO mice. Given that elevated APP protein expression can elicit Alzheimer's disease (AD) in patients and model systems, we evaluated whether FMRP expression might be altered in Alzheimer's autopsy brain samples and mouse models compared to controls. In a double transgenic mouse model of AD (APP/PS1), we found no difference in FMRP expression in aged AD model mice compared to littermate controls. FMRP expression was also similar in AD and control patient frontal cortex and cerebellum samples. Fragile X-associated tremor/ataxia syndrome (FXTAS) is an age-related neurodegenerative disorder caused by expanded CGG repeats in the 5' untranslated region of the FMR1 gene. Patients experience cognitive impairment and dementia in addition to motor symptoms. In parallel studies, we measured FMRP expression in cortex and cerebellum from three FXTAS patients and found reduced expression compared to both controls and Alzheimer's patient brains, consistent with animal models. We also find increased APP levels in cerebellar, but not cortical, samples of FXTAS patients compared to controls. Taken together, these data suggest that a decrease in FMRP expression is unlikely to be a primary contributor to Alzheimer's disease pathogenesis.
    Frontiers in Genetics 10/2014; 5:360. DOI:10.3389/fgene.2014.00360
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    • "Studies of Golgi-stained neurons have also revealed ultrastructural changes in dendrites and dendritic spines in both CGGdut and CGGnih KI mice [30,53]. The CGGdut KI mouse shows fewer dendritic branches proximal to the soma, reduced total dendritic length and longer dendritic spines on basilar, but not on apical dendrites in pyramidal neurons in the primary visual cortex. "
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    ABSTRACT: Carriers of the fragile X premutation (FPM) have CGG trinucleotide repeat expansions of between 55 and 200 in the 5'-UTR of FMR1, compared to a CGG repeat length of between 5 and 54 for the general population. Carriers were once thought to be without symptoms, but it is now recognized that they can develop a variety of early neurological symptoms as well as being at risk for developing the late onset neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Several mouse models have contributed to our understanding of FPM and FXTAS, and findings from studies using these models are summarized here. This review also discusses how this information is improving our understanding of the molecular and cellular abnormalities that contribute to neurobehavioral features seen in some FPM carriers and in patients with FXTAS. Mouse models show much of the pathology seen in FPM carriers and in individuals with FXTAS, including the presence of elevated levels of Fmr1 mRNA, decreased levels of fragile X mental retardation protein, and ubiquitin-positive intranuclear inclusions. Abnormalities in dendritic spine morphology in several brain regions are associated with neurocognitive deficits in spatial and temporal memory processes, impaired motor performance, and altered anxiety. In vitro studies have identified altered dendritic and synaptic architecture associated with abnormal Ca(2+) dynamics and electrical network activity. FPM mice have been particularly useful in understanding the roles of Fmr1 mRNA, fragile X mental retardation protein, and translation of a potentially toxic polyglycine peptide in pathology. Finally, the potential for using these and emerging mouse models for preclinical development of therapies to improve neurological function in FXTAS is considered.
    Journal of Neurodevelopmental Disorders 07/2014; 6(1):25. DOI:10.1186/1866-1955-6-25 · 3.27 Impact Factor
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    • "FMRP levels tend to decrease with increasing CGG repeat length, and in both KI models, brain FMRP levels are decreased; the effect size varies across studies (Willemsen et al., 2003; Brouwer et al., 2007, 2008a, 2008b; Entezam et al., 2007; Qin et al., 2011; Berman et al., 2012; Ludwig et al., 2014). Previously, we studied young adult, male KINIH PM mice with CGG(120–140) and found that they had a very similar behavioral phenotype to Fmr1 knockout (KO) mice (Qin et al., 2011). We found that young adult KINIH mice exhibited hyperactivity in the open field, less general anxiety in both the open field and elevated zero maze, impaired learning and memory on a passive avoidance test, and subtle deficits on a test of social interaction. "
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    ABSTRACT: The (CGG)n-repeat in the 5'-untranslated region of the fragile X mental retardation gene (FMR1) gene is polymorphic and may become unstable on transmission to the next generation. In fragile X syndrome, CGG repeat lengths exceed 200, resulting in silencing of FMR1 and absence of its protein product, fragile X mental retardation protein (FMRP). CGG repeat lengths between 55 and 200 occur in fragile X premutation (FXPM) carriers and have a high risk of expansion to a full mutation on maternal transmission. FXPM carriers have an increased risk for developing progressive neurodegenerative syndromes and neuropsychological symptoms. FMR1 mRNA levels are elevated in FXPM, and it is thought that clinical symptoms might be caused by a toxic gain of function due to elevated FMR1 mRNA. Paradoxically, FMRP levels decrease moderately with increasing CGG repeat length in FXPM. Lowered FMRP levels may also contribute to the appearance of clinical problems. We previously reported increases in regional rates of cerebral protein synthesis (rCPS) in the absence of FMRP in an Fmr1 knockout mouse model and in a FXPM knockin (KI) mouse model with 120 to 140 CGG repeats in which FMRP levels are profoundly reduced (80%-90%). To explore whether the concentration of FMRP contributes to the rCPS changes, we measured rCPS in another FXPM KI model with a similar CGG repeat length and a 50% reduction in FMRP. In all 24 brain regions examined, rCPS were unaffected. These results suggest that even with 50% reductions in FMRP, normal protein synthesis rates are maintained.
    ASN Neuro 07/2014; 6(5). DOI:10.1177/1759091414551957 · 4.02 Impact Factor
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