Transgenic mouse model for the fragile X syndrome

Kooy, R. Frank; D’Hooge, Rudi; Reyniers, Edwin; Bakker, Cathy; Nagels, Guy; Boulle, Kristel De; Storm, Katrien; Clincke, G.; Deyn, Peter Paul De; Oostra, Ben A.; Willems, Patrick J.

doi:10.1002/(sici)1096-8628(19960809)64:2<241::aid-ajmg1>3.0.co;2-x

Cited by 160 publications

(89 citation statements)

References 17 publications

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“…As in humans, Fmr1 knockout mice have macroorchidism, which is evident from PND 15 onwards and results in an increase of testicular weight by 30% after 6 months (Bakker et al, 1994;Kooy et al, 1996;Kooy et al, 1998). Dendritic spine abnormalities are a hallmark of FXS patients (Hinton et al, 1991) and this is recapitulated in Fmr1 knockout mice.…”

Section: The Mouse Model and Molecular Mechanisms Of Fragile X Syndromementioning

confidence: 99%

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Early developmental alterations in GABAergic protein expression in fragile X knockout mice

et al. 2010

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The purpose of this study was to examine the expression of GABAergic proteins in Fmr1 knockout mice during brain maturation and to assess behavioural changes potentially linked to perturbations in the GABAergic system. Quantitative western blotting of the forebrain revealed that compared to wild-type mice, the GABA A receptor α1, β2, and δ subunits, and the GABA catabolic enzymes GABA transaminase and SSADH were down-regulated during postnatal development, while GAD65 was up-regulated in the adult knockout mouse forebrain. In tests of locomotor activity, the suppressive effect on motor activity of the GABA A β2/3 subunit-selective drug loreclezole was impaired in the mutant mice. In addition, sleep time induced by the GABA A β2/3-selective anaesthetic drug etomidate was decreased in the knockout mice. Our results indicate that disruptions in the GABAergic system in the developing brain may result in behavioural consequences in adults with fragile X syndrome.iii

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Section: The Mouse Model and Molecular Mechanisms Of Fragile X Syndromementioning

confidence: 99%

“…Seizure incidence in knockout mice have been shown peak in the third week of postnatal life (Yan et al, 2005). Finally, several independent studies have shown knockout mice to be hyperactive in the open field test (Bakker et al, 1994;Kooy et al, 1996;Mineur et al, 2002).…”

Section: The Mouse Model and Molecular Mechanisms Of Fragile X Syndromementioning

confidence: 99%

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

et al. 2010

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“…48 The Fmrp (fragile X mental retardation protein)-deficient mouse, a model for FXS, exhibits marked susceptibility to audiogenic seizures [49][50][51] and evidences the enlarged testes, although not the facial dysmorphology, characteristic of the human disease. [51][52][53][54] Most studies report that the loss of Fmrp in mice does not lead to overt motor impairment, severe learning deficiencies, or a lack of social approach. Alterations in the behavioral phenotype of the Fmr1-null mouse include increased levels of social anxiety, 55 reduced social interaction, 56 hyperactivity, 52,57-60 and deficits in spatial learning on a radial arm maze 57 and reversal learning in the Morris water maze task 52,53,61 (see also Ref.…”

Section: Mouse Models Of Genetic Clinical Disorders With Autism Symptmentioning

confidence: 99%

“…[51][52][53][54] Most studies report that the loss of Fmrp in mice does not lead to overt motor impairment, severe learning deficiencies, or a lack of social approach. Alterations in the behavioral phenotype of the Fmr1-null mouse include increased levels of social anxiety, 55 reduced social interaction, 56 hyperactivity, 52,57-60 and deficits in spatial learning on a radial arm maze 57 and reversal learning in the Morris water maze task 52,53,61 (see also Ref. 62).…”

Section: Mouse Models Of Genetic Clinical Disorders With Autism Symptmentioning

confidence: 99%

Advances in behavioral genetics: mouse models of autism

2007

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Autism is a neurodevelopmental syndrome with markedly high heritability. The diagnostic indicators of autism are core behavioral symptoms, rather than definitive neuropathological markers. Etiology is thought to involve complex, multigenic interactions and possible environmental contributions. In this review, we focus on genetic pathways with multiple members represented in autism candidate gene lists. Many of these pathways can also be impinged upon by environmental risk factors associated with the disorder. The mouse model system provides a method to experimentally manipulate candidate genes for autism susceptibility, and to use environmental challenges to drive aberrant gene expression and cell pathology early in development. Mouse models for fragile X syndrome, Rett syndrome and other disorders associated with autistic-like behavior have elucidated neuropathology that might underlie the autism phenotype, including abnormalities in synaptic plasticity. Mouse models have also been used to investigate the effects of alterations in signaling pathways on neuronal migration, neurotransmission and brain anatomy, relevant to findings in autistic populations. Advances have included the evaluation of mouse models with behavioral assays designed to reflect disease symptoms, including impaired social interaction, communication deficits and repetitive behaviors, and the symptom onset during the neonatal period. Research focusing on the effect of gene-by-gene interactions or genetic susceptibility to detrimental environmental challenges may further understanding of the complex etiology for autism.

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“…An excess of dendritic spines in fragile X patients indicates a deficit in synaptic pruning. This pathology is also seen in mice that are deficient in FMRP whose pyramidal neurons show an excess of spines [Kooy et al, 1996]. Other forms of mental retardation seem to implicate synaptogenesis as a key step in cognitive development.…”

Section: Suggestive Evidence Linking Disruptions In Synaptogenesis Wimentioning

confidence: 95%

Synaptogenesis and heritable aspects of executive attention

Fossella

Sommer

Fan

et al. 2003

Ment. Retard. Dev. Disabil. Res. Rev.

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In humans, changes in brain structure and function can be measured non-invasively during postnatal development. In animals, advanced optical imaging measures can track the formation of synapses during learning and behavior. With the recent progress in these technologies, it is appropriate to begin to assess how the physiological processes of synapse, circuit, and neural network formation relate to the process of cognitive development. Of particular interest is the development of executive function, which develops more gradually in humans. One approach that has shown promise is molecular genetics. The completion of the human genome project and the human genome diversity project make it straightforward to ask whether variation in a particular gene correlates with variation in behavior, brain structure, brain activity, or all of the above. Strategies that unify the wealth of biochemical knowledge pertaining to synapse formation with the functional measures of brain structure and activity may lead to new insights in developmental cognitive psychology.

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Transgenic mouse model for the fragile X syndrome

Cited by 160 publications

References 17 publications

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

Advances in behavioral genetics: mouse models of autism

Synaptogenesis and heritable aspects of executive attention

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