Increased rates of cerebral glucose metabolism in a mouse model of fragile X mental retardation

Qin, Mei; Kang, Julia; Smith, Carolyn Beebe

doi:10.1073/pnas.242377399

Cited by 85 publications

(102 citation statements)

References 50 publications

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“…2 Similarly, whereas anxiety problems are prevalent in FXS patients, Fmr1-KO mice exhibit reduced anxiety. 8,32 Higher cognitive function is influenced by complex interactions between multiple genes. Therefore, in mouse models of inherited cognitive disorders, even subtle differences in compensatory mechanisms between humans and mice may amplify, blunt or alter the disease phenotype.…”

Section: Discussionmentioning

confidence: 99%

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Sensorimotor gating abnormalities in young males with fragile X syndrome and Fmr1-knockout mice

et al. 2004

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Fragile X syndrome (FXS) is the most common single gene (FMR1) disorder affecting cognitive and behavioral function in humans. This syndrome is characterized by a cluster of abnormalities including lower IQ, attention deficits, impairments in adaptive behavior and increased incidence of autism. Here, we show that young males with FXS have profound deficits in prepulse inhibition (PPI), a basic marker of sensorimotor gating that has been extensively studied in rodents. Importantly, the magnitude of the PPI impairments in the fragile X children predicted the severity of their IQ, attention, adaptive behavior and autistic phenotypes. Additionally, these measures were highly correlated with each other, suggesting that a shared mechanism underlies this complex phenotypic cluster. Studies in Fmr1-knockout mice also revealed sensorimotor gating and learning abnormalities. However, PPI and learning were enhanced rather than reduced in the mutants. Therefore, these data show that mutations of the FMR1 gene impact equivalent processes in both humans and mice. However, since these phenotypic changes are opposite in direction, they also suggest that murine compensatory mechanisms following loss of FMR1 function differ from those in humans.

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Section: Discussionmentioning

confidence: 99%

“…However, previous studies have shown that learning may be normal, 8,30,31 mildly impaired, 7,[30][31][32][33] or even improved 34 in Fmr1-KO mice. However, there are many different types of learning, 35 and the Fmr1-KO mutation may affect some forms more than others.…”

Section: Fmr1-ko Mice Exhibit Enhanced Ppimentioning

confidence: 91%

Sensorimotor gating abnormalities in young males with fragile X syndrome and Fmr1-knockout mice

et al. 2004

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“…Measures of learning and memory in a fear based paradigm were generally comparable for targeted and wild type alleles on a C57BL/6 background (Peier, McIlwain et al 2000), though these mice expressed reduced memory for avoidance in a leverpress paradigm compared to wild type (Brennan, Albeck et al 2006). Lack of functional FMR1 alleles on an FVB/NJ background resulted in deficits in a passive avoidance memory task (Qin, Kang et al 2002). The memory defect in gene-targeted mice C57BL/6J is not due to an FMRP-reduction of CREB, since CREB levels are comparable for targeted and wild type alleles (Li, Pelletier et al 2002).…”

Section: Fragile X Mousementioning

confidence: 90%

“…However, behavioral and physiological studies of mouse anxiety suggest abnormal, but not typically heightened anxiety responses in FMR1 knockout mice (For thorough review, see Bernardet and Crusio 2006). For example, in the FVB/NJ strain, knockout mice show reduced anxiety-related behavior in an open field test compared to wild type (Qin, Kang et al 2002). FMR1 knockouts on a C57BL/6 background, however, express heightened open field exploration and light-dark exploration relative to wild-type controls (Peier, McIlwain et al 2000).…”

Section: Fragile X Mousementioning

confidence: 99%

The cyclic AMP phenotype of fragile X and autism

Kelley

Bhattacharyya

Lahvis

et al. 2008

Neuroscience & Biobehavioral Reviews

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Cyclic AMP (cAMP) is a second messenger involved in many processes including mnemonic processing and anxiety. Memory deficits and anxiety are noted in the phenotype of fragile X (FX), the most common heritable cause of mental retardation and autism. Here we review reported observations of altered cAMP cascade function in FX and autism. Cyclic AMP is a potentially useful biochemical marker to distinguish autism comorbid with FX from autism per se and the cAMP cascade may be a viable therapeutic target for both FX and autism.

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“…they are hyperactive), whereas mice overexpressing FMRP display hypoactivity, suggesting that FMRP acts in a dose-dependent manner [48]. Moreover, increased rates of cerebral glucose metabolism have been observed in Fmr1-knockout mice; and the regions most affected are consistent with behavioral deficiencies and regions with highest FMRP expression [49]. Recently, Drosophila has been used as a model system to explore the function of FMRP.…”

Section: Ti Bsmentioning

confidence: 99%

New insights into fragile X syndrome: from molecules to neurobehaviors

Jin

Warren

2003

Trends in Biochemical Sciences

190

124

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Fragile X syndrome -a common form of inherited mental retardation -is caused by the loss of the fragile X mental retardation 1 protein (FMRP). FMRP is an RNA-binding protein which forms a messenger ribonucleoprotein (mRNP) complex that associates with translating polyribosomes. It has been proposed that FMRP is involved in synaptic plasticity through the regulation of mRNA transportation and translation. Recent advances in the identification of the mRNA ligands that are bound by FMRP, the RNA sequence and structure required for FMRP -RNA interaction, and the physiological consequences of FMRP deficiency in the brain are important steps towards understanding the molecular pathogenesis of fragile X syndrome, and learning and memory in general.Fragile X syndrome is the most common form of inherited mental retardation, with the estimated prevalence of one in 4000 males and one in 8000 females. In addition to cognitive deficits, the phenotype of fragile X syndrome includes mildly abnormal facial features (a prominent jaw, high forehead and large ears), MACROORCHIDISM (see Glossary) in postpubescent males and subtle connective tissue abnormalities [1]. Many patients also manifest attention-deficit hyperactivity disorder and autistic-like behavior. As one of the first identified human disorders caused by trinucleotide repeat expansion, fragile X syndrome is the result of a massive CGG trinucleotide repeat expansion within the gene fragile X mental retardation 1 (FMR1). FMR1 is a highly conserved gene that consists of 17 exons, and spans , 38 kilobases (kb). Within the 4.4-kb FMR1 transcript, a CGG trinucleotide repeat is located in the 5 0 untranslated region (UTR) [2]. Among normal individuals, this CGG repeat is highly polymorphic in length and content, often punctuated by AGG interruptions. The normal repeat size ranges from 7 to , 54, with 30 repeats found in the most common allele. In most affected individuals, CGG repeats are massively expanded over 230 repeats (full mutation) and become abnormally hypermethylated, which results in the transcriptional silencing of FMR1 [1]. Identification of other mutations in FMR1 (e.g. deletions and a point mutation among patients with the typical phenotype, but without FRAGILE SITE expression) has confirmed that the FMR1 gene is the only gene involved in the pathogenesis of fragile X syndrome and the loss of FMR1 product -fragile X mental retardation protein (FMRP) -causes fragile X syndrome [1]. A mouse model of fragile X syndrome was created using gene targeting; the Fmr1-knockout mice exhibit macroorchidism and subtle deficits in learning and memory, which mimic the human phenotype [3].In this review, we discuss the recent progress in understanding the biological functions of FMRP and the physiological consequences of its absence that lead to mental retardation. Features of FMRPFMRP is widely expressed in fetal and adult tissues, with the most abundant expression in brain and testes [4]. FMRP, and its autosomal paralogs the fragile-X-related protein FXR1P and FXR2P, consist...

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Increased rates of cerebral glucose metabolism in a mouse model of fragile X mental retardation

Cited by 85 publications

References 50 publications

Sensorimotor gating abnormalities in young males with fragile X syndrome and Fmr1-knockout mice

Sensorimotor gating abnormalities in young males with fragile X syndrome and Fmr1-knockout mice

The cyclic AMP phenotype of fragile X and autism

New insights into fragile X syndrome: from molecules to neurobehaviors

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