Fmr1 knockout mouse has a distinctive strain-specific learning impairment

Dobkin, Carl; Rabe, Ausma; Dumas, R; Idrissi, Abdeslem El; Haubenstock, H.; Brown, W. Ted

doi:10.1016/s0306-4522(00)00292-x

Cited by 163 publications

(162 citation statements)

References 57 publications

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“…188,191 The C57BL/6 mouse strain has been used as the background for many mutant lines, but studies in the fragile X-model mouse have suggested that this strain has less susceptibility to the effects of Fmrp deficiency. 51,61,65 C57BL/6J mice are also characterized by high-frequency hearing loss 337 and markedly low acquisition of a T-maze learning task, 17 indicating possible issues with using this strain as a background for mutant lines. Some findings suggest that the 129 strain confers greater susceptibility to gene disruption, 61,65 but, in the case of Ube3A-null mice, also leads to higher rates of seizures and mortality.…”

Section: Discussionmentioning

confidence: 99%

“…51,61,65 C57BL/6J mice are also characterized by high-frequency hearing loss 337 and markedly low acquisition of a T-maze learning task, 17 indicating possible issues with using this strain as a background for mutant lines. Some findings suggest that the 129 strain confers greater susceptibility to gene disruption, 61,65 but, in the case of Ube3A-null mice, also leads to higher rates of seizures and mortality. 89 The 129S1/SvImJ strain demonstrates low social approach in our three-chambered choice task, 17 which could confound the detection of social deficits in mutant mice with this background.…”

Section: Discussionmentioning

confidence: 99%

“…Some studies have found unchanged behavioral responses in FXS-model mice in tests of anxiety and activity, 63,64 fear conditioning, 58,62,64,65 spatial learning, 54,58 and aggression. 57 Dobkin et al 65 have suggested that differences in behavioral phenotype may be attributed, in part, to the effect of different genetic backgrounds of the mouse strains used for the Fmr1-null mice, with fewer effects observed in mice on a C57BL/6 background and greater effects in mice with a mixed background including the 129 strain (see also 61 ). A systematic evaluation of the mutation on two inbred backgrounds (C57BL/6J and FVB/NJ), including F 1 hybrid mice carrying the X-linked Fmr1-null allele, also found a generally mild behavioral phenotype, increased seizure susceptibility, and macroorchidism.…”

Section: Mouse Models Of Genetic Clinical Disorders With Autism Symptmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Mouse Models Of Genetic Clinical Disorders With Autism Symptmentioning

confidence: 99%

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Advances in behavioral genetics: mouse models of autism

2007

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“…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: 90%

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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“…Genetic background has long been known to influence the behavioral phenotype of mutant mice (Shanks and Anisman, 1988,Gerlai, 1996,Logue et al, 1997,Bouwknecht and Paylor, 2002,Schauwecker, 2002,McKhann et al, 2003,Sik et al, 2003,Waddell et al, 2004, but fewer studies have focused on the brain-based mechanisms for such strain dependence. Brain (Bilovocky et al, 2003) and limb (Murcia et al, 2004) phenotypes caused by mutation of the Engrailed-1 (en-1) gene are highly dependent upon genetic background, as are the neural phenotypes produced by mutations of p75NGF (Greferath et al, 2000), Unc5c (Burgess et al, 2006), fmr-1 (Paradee et al, 1999,Dobkin et al, 2000,Ivanco and Greenough, 2002,Mineur et al, 2002,Errijgers and Kooy, 2004 and Pax2 (Schwarz et al, 1997). Herrup and colleagues have identified one significant modifier and several other possible loci that may be responsible for trait differences in limb and cerebellum specification in the en-1 knockout (Murcia et al, 2004,Murcia et al, 2006, and a recent report identified a major modifier locus that influences phrenic motor axon guidance in the absence of Unc5c (Burgess et al, 2006).…”

Section: The Influence Of Genetic Background On the Expression Of Phementioning

confidence: 99%

Disruption of Foxg1 expression by knock-in of Cre recombinase: Effects on the development of the mouse telencephalon

et al. 2007

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The Cre/loxP system is used routinely to manipulate gene expression in the mouse nervous system. In order to delete genes specifically from the telencephalon, the Foxg1-cre line was created previously by replacing the intron-less Foxg1 coding region with cre, resulting in a Foxg1 heterozygous mouse. As the telencephalon of heterozygous Foxg1 mice was reported to be normal, this genotype often has been used as the control in subsequent analyses. Here we describe substantial disruption of forebrain development of heterozygous mice in the Foxg1-cre line, maintained on the C57BL/6J background. High resolution magnetic resonance microscopy reveals a significant reduction in the volume of the neocortex, hippocampus and striatum. The alteration in the neocortex results, in part, from a decrease in its tangential dimension, although gross patterning of the cortical sheet appears normal. This decrease is observed in three different Foxg1 heterozygous mouse lines, independent of the method of achieving deletion of the Foxg1 gene. Although Foxg1 is not expressed in the diencephalon, three-dimensional magnetic resonance microscopy revealed that thalamic volume in the adult is reduced. In contrast, at postnatal day 4, thalamic volume is normal, suggesting that interactions between cortex and dorsal thalamus postnatally produce the final adult thalamic phenotype. In the Foxg1-cre line maintained on the C57BL/6J background, the radial domain of the cerebral cortex also is disrupted substantially, particularly in supragranular layers. However, neither Foxg1 heterozygous mice of the Foxg1-tet line, nor those of the Foxg1-lacZ and Foxg1-cre lines maintained on a mixed background, displayed a reduced cortical thickness. Thus Cre recombinase contributes to the radial phenotype, although only in the context of the congenic C57BL/6J background. These observations highlight an important role for Foxg1 in cortical development, reveal noteworthy complexity in the invocation of specific mechanisms underlying phenotypes expressed following genetic manipulations and stress the importance of including appropriate controls of all genotypes. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Development of the cerebral cortex relies on extracellular cues and intrinsic signals that instruct the proliferation, differentiation and migration of neuronal precursors. The duration and location of these cues are critical to producing the final cortical architecture (FukuchiShimogori and Grove, 2001, Parnavelas et al., 2002, Rakic, 2002, Shimogori et al., 2004, Rash and Grove, 2006, Storm et al., 2006. The...

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Fmr1 knockout mouse has a distinctive strain-specific learning impairment

Cited by 163 publications

References 57 publications

Advances in behavioral genetics: mouse models of autism

Advances in behavioral genetics: mouse models of autism

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

Disruption of Foxg1 expression by knock-in of Cre recombinase: Effects on the development of the mouse telencephalon

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