Article

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: 3.25). 12/2009; 123(6):1315-24. DOI: 10.1037/a0017616
Source: PubMed

ABSTRACT 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, Jul 28, 2015
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    • "These findings are important because reduced dendrite complexity and altered spine morphology could underlie, at least in part, behavioral impairments reported in CGG KI mice. These impairments include processing of visual spatial information (Hunsaker et al., 2009), temporal information (Hunsaker et al., 2010), and poor visual-motor coordination in a test of locomotor coordination (Hunsaker et al., 2011). "
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    ABSTRACT: The fragile X mental retardation 1 gene (Fmr1) is polymorphic for CGG trinucleotide repeat number in the 5'-untranslated region, with repeat lengths <45 associated with typical development and repeat lengths >200 resulting in hypermethylation and transcriptional silencing of the gene and mental retardation in the fragile X Syndrome (FXS). Individuals with CGG repeat expansions between 55 and 200 are carriers of the fragile X premutation (PM). PM carriers show a phenotype that can include anxiety, depression, social phobia, and memory deficits. They are also at risk for developing fragile X-associated tremor/ataxia syndrome (FXTAS), a late onset neurodegenerative disorder characterized by tremor, ataxia, cognitive impairment, and neuropathologic features including intranuclear inclusions in neurons and astrocytes, loss of Purkinje cells, and white matter disease. However, very little is known about dendritic morphology in PM or in FXTAS. Therefore, we carried out a Golgi study of dendritic complexity and dendritic spine morphology in layer II/III pyramidal neurons in primary visual cortex in a knock-in (KI) mouse model of the PM. These CGG KI mice carry an expanded CGG trinucleotide repeat on Fmr1, and model many features of the PM and FXTAS. Compared to wild-type (WT) mice, CGG KI mice showed fewer dendritic branches proximal to the soma, reduced total dendritic length, and a higher frequency of longer dendritic spines. The distribution of morphologic spine types (e.g., stubby, mushroom, filopodial) did not differ between WT and KI mice. These findings demonstrate that synaptic circuitry is abnormal in visual cortex of mice used to model the PM, and suggest that such changes may underlie neurologic features found in individuals carrying the PM as well as in individuals with FXTAS.
    Epilepsia 06/2012; 53 Suppl 1:150-60. DOI:10.1111/j.1528-1167.2012.03486.x · 4.58 Impact Factor
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    • "This type of processing refers to the role of the brain in determining the locations of objects within spatial with mathematical precision (i.e., precise angles and distances among objects in space, as well as how the individual fits into that " cognitive map " ). There are a number of tasks that probe this type of spatial processing, particularly those evaluating spatial pattern separation (Bartko et al., 2011; Hunsaker et al., 2009), a process proposed to be disrupted in a number of genetic disorders (cf., Hanson and Madison, 2010). These tasks evaluate the ability of mice to specifically determine spatial relationships among stimuli in ways similar to studies in humans (cf., Goodrich-Hunsaker et al., 2011a; Kessels et al., 2010; Kosslyn, 2006; Kosslyn et al., 1989, 1992). "
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    ABSTRACT: There is a need for refinement of the current behavioral phenotyping methods for mouse models of genetic disorders. The current approach is to perform a behavioral screen using standardized tasks to define a broad phenotype of the model. This phenotype is then compared to what is known concerning the disorder being modeled. The weakness inherent in this approach is twofold: First, the tasks that make up these standard behavioral screens do not model specific behaviors associated with a given genetic mutation but rather phenotypes affected in various genetic disorders; secondly, these behavioral tasks are insufficiently sensitive to identify subtle phenotypes. An alternate phenotyping strategy is to determine the core behavioral phenotypes of the genetic disorder being studied and develop behavioral tasks to evaluate specific hypotheses concerning the behavioral consequences of the genetic mutation. This approach emphasizes direct comparisons between the mouse and human that facilitate the development of neurobehavioral biomarkers or quantitative outcome measures for studies of genetic disorders across species.
    Progress in Neurobiology 02/2012; 96(2):220-41. DOI:10.1016/j.pneurobio.2011.12.001 · 10.30 Impact Factor
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    • "In the best characterized of the models (Willemsen et al., 2003; Berman and Willemsen, 2009), CGG KI mice show signs of hippocampal-dependent cognitive impairment at an early age that precedes frank neurodegeneration or inclusion formation (Hunsaker et al., 2009). These same mice also show signs of age dependent cognitive decline in later life as measured by impaired visual-spatial learning and performance on the Morris water maze (Van Dam et al., 2005). "
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    ABSTRACT: The expression, processing, transport and activities of both coding and non-coding RNAs play critical roles in normal neuronal function and differentiation. Over the past decade, these same pathways have come under scrutiny as potential contributors to neurodegenerative disease. Here we focus broadly on the roles of RNA and RNA processing in neurodegeneration. We first discuss a set of "RNAopathies", where non-coding repeat expansions drive pathogenesis through a surprisingly diverse set of mechanisms. We next explore an emerging class of "RNA binding proteinopathies" where redistribution and aggregation of the RNA binding proteins TDP-43 or FUS contribute to a potentially broad range of neurodegenerative disorders. Lastly, we delve into the potential contributions of alterations in both short and long non-coding RNAs to neurodegenerative illness.
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