Article

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: 5.2). 04/2011; 42(1):85-98. DOI: 10.1016/j.nbd.2011.01.008
Source: PubMed

ABSTRACT 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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    • "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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    • "FXS is caused by trinucleotide repeat expansions of an X-linked gene, FMR1, which results in the transcriptional silencing and loss of the FMR1 protein product, the fragile X mental retardation protein (FMRP; reviewed in Penagarikano et al., 2007; Bagni et al., 2012). Brains of FXS patients and FMR1 knockout mice show abnormal morphology of dendritic spines (Rudelli et al., 1985; Hinton et al., 1991; Comery et al., 1997; Irwin et al., 2001, 2002; McKinney et al., 2005; Levenga et al., 2011) and dendritic arborizations (Braun and Segal, 2000; Galvez et al., 2003, 2005; Castr en et al., 2005; Restivo et al., 2005; Zarnescu et al., 2005; Thomas et al., 2008; Qin et al., 2011; Scotto- Lomassese et al., 2011; Till et al., 2012). "
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