A mouse model of fragile X syndrome exhibits heightened arousal and/or emotion following errors or reversal of contingencies

Moon, Jisook; Ota, Koshi; Driscoll, Lori; Levitsky, David A.; Strupp, Barbara J.

doi:10.1002/dev.20308

Cited by 17 publications

(19 citation statements)

References 63 publications

(77 reference statements)

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“…This suggests the KO mice overreacted and may have tried to represent the environment differently, whereas the WT mice did not express an unusual pattern of theta-gamma PAC, and as such probably did not change the representation of the environment. These observations extend behavioral observations of exaggerated responses to environmental change in Fmr1 KO mice (Moon et al, 2006; Moon et al, 2008) by demonstrating an exaggerated adjustment of representational neural activity in the KO mice upon experiencing changes in the location of shock (Figs. 3,4 and 5).…”

Section: Discussionsupporting

confidence: 82%

Impaired cognitive discrimination and discoordination of coupled theta–gamma oscillations in Fmr1 knockout mice

Radwan

Dvořák

Fenton

2016

Neurobiology of Disease

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Fragile X syndrome (FXS) patients do not make the fragile X mental retardation protein (FMRP). Absence of FMRP causes dysregulated translation, abnormal synaptic plasticity and the most common form of inherited intellectual disability. But FMRP loss has minimal effects on memory itself, making it difficult to understand why absence of FMRP impairs memory discrimination and increases risk of autistic symptoms in patients, such as exaggerated responses to environmental changes. While Fmr1 knockout (KO) and wild-type (WT) mice perform cognitive discrimination tasks, we find abnormal patterns of coupling between theta and gamma oscillations in perisomatic and dendritic hippocampal CA1 local field potentials of the KO. Perisomatic CA1 theta-gamma phase-amplitude coupling (PAC) decreases with familiarity in both the WT and KO, but activating an invisible shock zone, subsequently changing its location, or turning it off, changes the pattern of oscillatory events in the LFPs recorded along the somato-dendritic axis of CA1. The cognition-dependent changes of this pattern of neural activity are relatively constrained in WT mice compared to KO mice, which exhibit abnormally weak changes during the cognitive challenge caused by changing the location of the shock zone and exaggerated patterns of change when the shock zone is turned off. Such pathophysiology might explain how dysregulated translation leads to intellectual disability in FXS. These findings demonstrate major functional abnormalities after the loss of FMRP in the dynamics of neural oscillations and that these impairments would be difficult to detect by steady-state measurements with the subject at rest or in steady conditions.

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Section: Discussionsupporting

confidence: 82%

Impaired cognitive discrimination and discoordination of coupled theta–gamma oscillations in Fmr1 knockout mice

Radwan

Dvořák

Fenton

2016

Neurobiology of Disease

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“…Beaudin et al, 2007; Gendle et al, 2003; Morgan et al, 2002; Stangle et al, 2007), mice (e.g. Moon et al, 2010, 2008), and humans (see Segalowitz and Dywan, 2009 for a review). This error-induced disruption in performance was exacerbated by dietary folate deficiency, suggesting an affective response that is either heightened or less well regulated.…”

Section: Discussionmentioning

confidence: 99%

Dietary and genetic manipulations of folate metabolism differentially affect neocortical functions in mice

Ash

Jiang

Malysheva

et al. 2013

Neurotoxicology and Teratology

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Converging evidence suggests that folate-mediated one-carbon metabolism may modulate cognitive functioning throughout the lifespan, but few studies have directly tested this hypothesis. This study examined the separate and combined effects of dietary and genetic manipulations of folate metabolism on neocortical functions in mice, modeling a common genetic variant in the MTHFD1 gene in humans. Mutant (Mthfd1gt/+) and wildtype (WT) male mice were assigned to a folate sufficient or deficient diet at weaning and continued on these diets throughout testing on a series of visual attention tasks adapted from the 5-choice serial reaction time task. WT mice on a deficient diet exhibited impulsive responding immediately following a change in task parameters that increased demands on attention and impulse control, and on trials following an error. This pattern of findings indicates a heightened affective response to stress and/or an inability to regulate negative emotions. In contrast, Mthfd1gt/+ mice (regardless of diet) exhibited attentional dysfunction and a blunted affective response to committing an error. The Mthfd1gt/+ mice also showed significantly decreased expression levels for genes encoding choline dehydrogenase and the alpha 7 nicotinic cholinergic receptor. The effects of the MTHFD1 mutation were less pronounced when combined with a deficient diet, suggesting a compensatory mechanism to the combined genetic and dietary perturbation of folate metabolism. These data demonstrate that common alterations in folate metabolism can produce functionally distinct cognitive and affective changes, and highlight the importance of considering genotype when making dietary folate recommendations.

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“…Fmr1 KO mice needed significantly more time to complete the task, as observed by the increased number of errors per trial during the training period ); however, they were able to complete the task. Additionally, mutant mice performed normally in the "olfactory discrimination task" (Mineur et al 2002;Yan et al 2004;Moon et al 2008;Guo et al 2011), suggesting that working memory (which correlates with IQ in humans) is not affected.…”

Section: Associative Learningmentioning

confidence: 99%

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

2014

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The Fragile X syndrome (FXS) is the most frequent form of inherited mental disability and is considered a monogenic cause of autism spectrum disorder. FXS is caused by a triplet expansion that inhibits the expression of the FMR1 gene. The gene product, the Fragile X Mental Retardation Protein (FMRP), regulates mRNA metabolism in brain and nonneuronal cells. During brain development, FMRP controls the expression of key molecules involved in receptor signaling, cytoskeleton remodeling, protein synthesis and, ultimately, spine morphology. Symptoms associated with FXS include neurodevelopmental delay, cognitive impairment, anxiety, hyperactivity, and autistic-like behavior. Twenty years ago the first Fmr1 KO mouse to study FXS was generated, and several years later other key models including the mutant Drosophila melanogaster, dFmr1, have further helped the understanding of the cellular and molecular causes behind this complex syndrome. Here, we review to which extent these biological models are affected by the absence of FMRP, pointing out the similarities with the observed human dysfunction. Additionally, we discuss several potential treatments under study in animal models that are able to partially revert some of the FXS abnormalities.

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A mouse model of fragile X syndrome exhibits heightened arousal and/or emotion following errors or reversal of contingencies

Cited by 17 publications

References 63 publications

Impaired cognitive discrimination and discoordination of coupled theta–gamma oscillations in Fmr1 knockout mice

Impaired cognitive discrimination and discoordination of coupled theta–gamma oscillations in Fmr1 knockout mice

Dietary and genetic manipulations of folate metabolism differentially affect neocortical functions in mice

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

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