Fragile X mice have robust mGluR5-dependent alterations of social behaviour in the Automated Tube Test

Esch, Celine de; Berg, Wouter E. van den; Buijsen, Ronald A.M.; Jaafar, I.A.; Nieuwenhuizen-Bakker, Ingeborg; Gasparini, F.; Kushner, Steven A.; Willemsen, Rob

doi:10.1016/j.nbd.2014.12.021

Cited by 39 publications

(38 citation statements)

References 60 publications

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“…In the first ERK1/2 study (tissue lysates), we observed a ~20% increase in hippocampal and striatal ERK1/2 activation from SAL-treated Fmr1 KO mice compared to SAL-treated WT mice. This effect has been observed by others using similar techniques [7, 36, 37]. Chronic acamprosate treatment significantly reduced ERK1/2 activation in lysates from both brain regions assessed in acamprosate-treated KO mice compared to control-treated KO mice, indicating a treatment effect.…”

Section: Discussionsupporting

confidence: 84%

Acamprosate in a mouse model of fragile X syndrome: modulation of spontaneous cortical activity, ERK1/2 activation, locomotor behavior, and anxiety

Schaefer

Davenport

Grainger

et al. 2017

J Neurodevelop Disord

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BackgroundFragile X Syndrome (FXS) occurs as a result of a silenced fragile X mental retardation 1 gene (FMR1) and subsequent loss of fragile X mental retardation protein (FMRP) expression. Loss of FMRP alters excitatory/inhibitory signaling balance, leading to increased neuronal hyperexcitability and altered behavior. Acamprosate (the calcium salt of N-acetylhomotaurinate), a drug FDA-approved for relapse prevention in the treatment of alcohol dependence in adults, is a novel agent with multiple mechanisms that may be beneficial for people with FXS. There are questions regarding the neuroactive effects of acamprosate and the significance of the molecule’s calcium moiety. Therefore, the electrophysiological, cellular, molecular, and behavioral effects of acamprosate were assessed in the Fmr1 -/y (knock out; KO) mouse model of FXS controlling for the calcium salt in several experiments.Methods Fmr1 KO mice and their wild-type (WT) littermates were utilized to assess acamprosate treatment on cortical UP state parameters, dendritic spine density, and seizure susceptibility. Brain extracellular-signal regulated kinase 1/2 (ERK1/2) activation was used to investigate this signaling molecule as a potential biomarker for treatment response. Additional adult mice were used to assess chronic acamprosate treatment and any potential effects of the calcium moiety using CaCl2 treatment on behavior and nuclear ERK1/2 activation.ResultsAcamprosate attenuated prolonged cortical UP state duration, decreased elevated ERK1/2 activation in brain tissue, and reduced nuclear ERK1/2 activation in the dentate gyrus in KO mice. Acamprosate treatment modified behavior in anxiety and locomotor tests in Fmr1 KO mice in which control-treated KO mice were shown to deviate from control-treated WT mice. Mice treated with CaCl2 were not different from saline-treated mice in the adult behavior battery or nuclear ERK1/2 activation.ConclusionsThese data indicate that acamprosate, and not calcium, improves function reminiscent of reduced anxiety-like behavior and hyperactivity in Fmr1 KO mice and that acamprosate attenuates select electrophysiological and molecular dysregulation that may play a role in the pathophysiology of FXS. Differences between control-treated KO and WT mice were not evident in a recognition memory test or in examination of acoustic startle response/prepulse inhibition which impeded conclusions from being made about the treatment effects of acamprosate in these instances.Electronic supplementary materialThe online version of this article (doi:10.1186/s11689-017-9184-y) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 84%

Acamprosate in a mouse model of fragile X syndrome: modulation of spontaneous cortical activity, ERK1/2 activation, locomotor behavior, and anxiety

Schaefer

Davenport

Grainger

et al. 2017

J Neurodevelop Disord

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“…For a more extensive review of Fmr1 knockout mice behavioral phenotypes see [180]. Behavior: social dominance [119]; sociability [132] Cognition: object recognition (chronic, not acute) [121]; fear conditioning [120]; associative motor learning (acute) [133]; inhibitory avoidance (chronic and acute) [129,133]; extinction memory (chronic) [129] LTP deficits in the amygdala and hippocampus (bath application) [128,134]; LTD (bath application) [135] startle response, † rotarod performance [131]; object recognition (acute) [121,134]; coordinate and categorical tasks (acute) [134]; analgesic response [121] mGlu5 NAMs used:…”

Section: Macro-orchidismmentioning

confidence: 99%

“…• MPEP [43,62,63,97,123,126,128,130,131,134] • MTEP [121] • Fenobam [124,126,133] • AFQ056 [119,125,127,132] CTEP [120,129] mGlu1 Genetic (het) Hyperexcitability: locomotor activity [118] Macro-orchidism, PPI, startle response, AGS, social interaction [118] Pharm Hyperexcitability: AGS (partially) [131] Startle response, rotarod [131] Muscarinic R (subtypes M1 and M4) Genetic (het) Plasticity and hyperexcitability: analgesic response, startle response (M4) [136] PPI, MB, light-dark transition (anxiety), AGS, macro-orchidism [136] Pharm Plasticity and hyperexcitability: AGS (M1+M4) [137,138] Cognition: passive avoidance (M4) [138] Passive avoidance (M1) [137] Group II mGlu N/A GSK3β antagonists used:…”

Section: Macro-orchidismmentioning

confidence: 99%

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Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

et al. 2015

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Fragile X syndrome (FXS), an inherited intellectual disability often associated with autism, is caused by the loss of expression of the fragile X mental retardation protein. Tremendous progress in basic, preclinical, and translational clinical research has elucidated a variety of molecular-, cellular-, and system-level defects in FXS. This has led to the development of several promising therapeutic strategies, some of which have been tested in larger-scale controlled clinical trials. Here, we will summarize recent advances in understanding molecular functions of fragile X mental retardation protein beyond the well-known role as an mRNAbinding protein, and will describe current developments and emerging limitations in the use of the FXS mouse model as a preclinical tool to identify therapeutic targets. We will review the results of recent clinical trials conducted in FXS that were based on some of the preclinical findings, and discuss how the observed outcomes and obstacles will inform future therapy development in FXS and other autism spectrum disorders.Key Words Fragile X syndrome . FMRP . mRNA translation . clinical trials . biomarkers . language development Fragile X syndrome (FXS) is one of the first single gene disorders manifesting features of autism spectrum disorder (ASD) in which extensive study of the neurobiology and synaptic mechanisms of disease in cellular and animal models has been possible. The enormous progress in basic and preclinical and clinical translational work in FXS in the last several decades has allowed FXS to emerge as an important model to illustrate successes and hurdles in the development of future targeted treatments for autism and related developmental disorders. FXS is the most common known genetic cause of intellectual disability and ASD, with an estimated frequency of about 1 in 4000-5000 [1]. The disorder affects all ethnic groups worldwide. Genetics and Phenotype of FXSFXS is one of the fragile X-associated disorders (FXDs), all of which arise from a trinucleotide repeat (CGG) expansion mutation in the promoter region of FMR1. The CGG sequence is transcribed into the 5' untranslated region of FMR1 mRNA and thus length of the repeat sequence does not affect the sequence of the protein product of FMR1 [fragile X mental retardation protein (FMRP)] [2]. Small expansions in the gene (55-200 CGG repeats), termed the Bpremutation^, occur in about 1 in 430-468 males and 1 in 151-209 females in the USA [3,4], and is associated with risk for fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Although the premutation is transcribed and translated to give FMRP, toxicity in fragile X-associated tremor/ataxia

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“…Only males were used, because of the X‐linked nature of FXS and because females are known to have a different phenotype in the automated tube test (van den Berg, Lamballais, & Kushner, ). Animals used in the automated tube test were housed individually after weaning, 3–4 weeks postpartum, as housing is known to influence the mice behavior (de Esch et al., ). For the three‐chamber sociability test, animals were group‐housed with 3–4 males per cage, with a mixed genotype.…”

Section: Methodsmentioning

confidence: 99%

Paradoxical effect of baclofen on social behavior in the fragile X syndrome mouse model

et al. 2018

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IntroductionFragile X syndrome (FXS) is a common monogenetic cause of intellectual disability, autism spectrum features, and a broad range of other psychiatric and medical problems. FXS is caused by the lack of the fragile X mental retardation protein (FMRP), a translational regulator of specific mRNAs at the postsynaptic compartment. The absence of FMRP leads to aberrant synaptic plasticity, which is believed to be caused by an imbalance in excitatory and inhibitory network functioning of the synapse. Evidence from studies in mice demonstrates that GABA, the major inhibitory neurotransmitter in the brain, and its receptors, is involved in the pathogenesis of FXS. Moreover, several FXS phenotypes, including social behavior deficits, could be corrected in Fmr1 KO mice after acute treatment with GABAB agonists.MethodsAs FXS would probably require a lifelong treatment, we investigated the effect of chronic treatment with the GABAB agonist baclofen on social behavior in Fmr1 KO mice on two behavioral paradigms for social behavior: the automated tube test and the three‐chamber sociability test.ResultsUnexpectedly, chronic baclofen treatment resulted in worsening of the FXS phenotypes in these behavior tests. Strikingly, baclofen treatment also affected wild‐type animals in both behavioral tests, inducing a phenotype similar to that of untreated Fmr1 KO mice.ConclusionAltogether, the disappointing results of recent clinical trials with the R‐baclofen enantiomer arbaclofen and our current results indicate that baclofen should be reconsidered and further evaluated before its application in targeted treatment for FXS.

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Fragile X mice have robust mGluR5-dependent alterations of social behaviour in the Automated Tube Test

Cited by 39 publications

References 60 publications

Acamprosate in a mouse model of fragile X syndrome: modulation of spontaneous cortical activity, ERK1/2 activation, locomotor behavior, and anxiety

Acamprosate in a mouse model of fragile X syndrome: modulation of spontaneous cortical activity, ERK1/2 activation, locomotor behavior, and anxiety

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

Paradoxical effect of baclofen on social behavior in the fragile X syndrome mouse model

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