Progressive Spatial Processing Deficits in a Mouse Model of the Fragile X Premutation

Program in Neuroscience, University of California, Davis, Davis, CA 95616, USA.
Behavioral Neuroscience (Impact Factor: 2.73). 12/2009; 123(6):1315-24. DOI: 10.1037/a0017616
Source: PubMed


Fragile X associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that is the result of a CGG trinucleotide repeat expansion in the range of 55-200 in the 5' UTR of the FMR1 gene. To better understand the progression of this disorder, a knock-in (CGG KI) mouse was developed by substituting the mouse CGG8 trinucleotide repeat with an expanded CGG98 repeat from human origin. It has been shown that this mouse shows deficits on the water maze at 52 weeks of age. In the present study, this CGG KI mouse model of FXTAS was tested on behavioral tasks that emphasize spatial information processing. The results demonstrate that at 12 and 24 weeks of age, CGG KI mice were unable to detect a change in the distance between two objects (metric task), but showed intact detection of a transposition of the objects (topological task). At 48 weeks of age, CGG KI mice were unable to detect either change in object location. These data indicate that hippocampal-dependent impairments in spatial processing may occur prior to parietal cortex-dependent impairments in FXTAS.

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Available from: Robert F Berman
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    • "Purkinje cell loss is seen in postmortem tissue from FXTAS brains, as well as in the CGGnih KI mouse, but has not been reported in the CGGdut KI mouse [26]. Behaviorally, there is evidence for memory impairment in both models [29,30], but the CGGdut KI mouse shows increased anxiety [31] whereas the CGGnih KI mouse shows decreased anxiety [30]. Both models show modest intergenerational repeat instability. "
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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.
    Full-text · Article · Jul 2014 · Journal of Neurodevelopmental Disorders
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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.
    Full-text · Article · Jul 2014 · ASN Neuro
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    • "To examine the contribution of the PM allele to the patient’s decline during aging we asked whether intranuclear inclusions were present in this individual that would suggest the presence of FXTAS pathology. Throughout this examination we largely focused on the granule cell population as studies in the CGG KI mouse model of PM have shown similar numbers of inclusions in cerebellar, olfactory bulb, and hippocampal granule cell populations [31-33]. Intranuclear inclusions were observed in three different regions of the brain (Figure 4). "
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    ABSTRACT: Lack of the fragile X mental retardation protein leads to Fragile X syndrome (FXS) while increased levels of FMR1 mRNA, as those observed in premutation carriers can lead to Fragile X- associated tremor ataxia syndrome (FXTAS). Until recently, FXTAS had been observed only in carriers of an FMR1 premutation (55–200 CGG repeats); however the disorder has now been described in individuals carriers of an intermediate allele (45–54 CGG repeats) as well as in a subject with a full mutation with mosaicism. Here, we report on molecular and clinical data of a male FMR1 mosaic individual with full and premutation alleles. Molecular analysis of FMR1 and FMRP expression in this subject is consistent with a FXS phenotype. We observed reduced expression of FMRP in both peripheral blood and brain leading to the FXS diagnosis. In addition, a dramatic 90% depletion of both FMR1 mRNA and FMRP levels was observed in the blood, as normally observed in FXS cases, and an even greater depletion in the brain. A clinical report of this patient, at age 71, described neurodegenerative signs of parkinsonism that were likely, in retrospect, part of a FXTAS scenario as post-mortem examination shows the presence of intranuclear inclusions, the hallmark pathology of FXTAS. The findings presented in this study indicate co-morbidity for both FXS and FXTAS in this individual carrying both full and premutation FMR1 alleles. In addition, based on symptoms and pathological and molecular evidence, this report suggests the need to redefine the diagnostic criteria of FXTAS.
    Full-text · Article · May 2013 · Translational Neurodegeneration
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