Motor deficits on a ladder rung task in male and female adolescent and adult CGG knock-in mice

Department of Neurological Surgery, School of Medicine, University of California, Davis
Behavioural brain research (Impact Factor: 3.03). 03/2011; 222(1):117-21. DOI: 10.1016/j.bbr.2011.03.039
Source: PubMed


The fragile X premutation is a tandem CGG trinucleotide repeat expansion on the FMR1 gene between 55 and 200 repeats in length. A CGG knock-in (CGG KI) mouse with CGG trinucleotide repeat lengths between 70 and 350 has been developed and used to model the histopathology and cognitive deficits reported in carriers of the fragile X premutation. Previous studies have shown that CGG KI mice show progressive deficits in processing spatial and temporal information. To characterize the motor deficits associated with the fragile X premutation, male and female CGG KI mice ranging from 2 to 16 months of age with trinucleotide repeats ranging from 72 to 240 CGG in length were tested for their ability to perform a skilled ladder rung walking test. The results demonstrate that both male and female CGG KI mice showed a greater number of foot slips as a function of increased CGG repeat length, independent of the age of the animal or general activity level.

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    • "In addition, sensory-motor coordination is impaired in adult CGGdut KI animals when they are required to traverse a horizontal ladder (the ladder rung task). Both male and female CGGdut KI mice showed impairments that were positively correlated with CGG repeat size [101]. Poor performance in the rotarod and ladder rung test may reflect the ataxia seen in FXTAS. "
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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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    • "As in the human disease, the KI mice in both models exhibit repeat-length instabilities on transmission to succeeding generations and a direct relationship between repeat number and Fmr1 mRNA levels in brain (Bontekoe et al., 2001; Entezam et al., 2007). KI mice also display behavioral phenotypes similar to those seen in human FXPM individuals, such as motor deficits, anxiety, and impairments of learning and memory (Van Dam et al., 2005; Hunsaker et al., 2009, 2011, 2012; Qin et al., 2011; Diep et al., 2012). 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). "
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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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    • "Notably, it was recently reported that Glu uptake is reduced in cortical extracts of the FMR1 KO mice, although this is thought to be mediated by GLT1; downregulation of mGluR5 and GLAST were also observed in these fractions at early but not at later developmental stages (Higashimori et al., 2013). The preCGG KI mice show rotarod deficits (Van Dam et al., 2005), and subtle but significant increased foot slips on the ladder-rung test that could be analogous to a mild ataxia (Hunsaker et al., 2011), and poor skilled forelimb motor Fig. 4. GRM5 messenger RNA (mRNA) and mGluR5 protein expression levels. Scatter plots show mGluR5 expression as a function of CGG length. "
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    ABSTRACT: A premutation (PM) expansion (55-200 CGG) in the fragile X mental retardation gene 1 causes elevated messenger RNA and reduced fragile X mental retardation gene 1 protein. Young PM carriers can develop characteristic physical features and mild cognitive disabilities. In addition, individuals with PM, particularly male carriers, are at high risk to develop fragile X-associated tremor/ataxia syndrome (FXTAS) with aging. Human postmortem FXTAS brains show extensive white matter disease in the cerebellum and the presence of intranuclear inclusions throughout the brain, although their etiologic significance is unknown. In the current work, expression levels of the metabotropic glutamate (Glu) receptor 5 and the Glu transporter excitatory amino acid transporter 1, examined by reverse transcription polymerase chain reaction and western blot analyses, were found to be reduced in the postmortem cerebellum of PM carriers with FXTAS compared with age matched controls, with higher CGG repeat number having greater reductions in both proteins. These data suggests a dysregulation of Glu signaling in PM carriers, which would likely contribute to the development and severity of FXTAS.
    Neurobiology of aging 11/2013; 35(5). DOI:10.1016/j.neurobiolaging.2013.11.009 · 5.01 Impact Factor
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