Modulation of behavioral phenotypes by a muscarinic M1 antagonist in a mouse model of fragile X syndrome

Veeraragavan, Surabi; Bui, Nghiem; Perkins, Jennie R.; Yuva-Paylor, Lisa A.; Carpenter, Randall L.; Paylor, Richard

doi:10.1007/s00213-011-2276-6

Cited by 57 publications

(72 citation statements)

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“…In a seminal article where the investigators generated six Fmr1 KO mouse strains, increases in marble burying were observed in only one of the tested strains, though no effect of Fmr1 deletion on marble burying behavior was noted across all strains. One other paper found a deficit in marble burying behavior that was only trending toward a statistically significant difference (Veeraragavan et al., 2011). In both studies only males were used, whereas our study reports the novel finding of female‐specific increases in the repetitive behavior of Fmr1 KOs on the nose‐poke task.…”

Section: Discussionmentioning

confidence: 99%

Deletion of Fmr1 results in sex‐specific changes in behavior

et al. 2017

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ObjectiveIn this study, we used a systemic Fmr1 knockout in order to investigate both genotype‐ and sex‐specific differences across multiple measures of sociability, repetitive behaviors, activity levels, anxiety, and fear‐related learning and memory.BackgroundFragile X syndrome is the most common monogenic cause of intellectual disability and autism. Few studies to date have examined sex differences in a mouse model of Fragile X syndrome, though clinical data support the idea of differences in both overall prevalence and phenotype between the sexes.MethodsUsing wild‐type and systemic homozygous Fmr1 knockout mice, we assessed a variety of behavioral paradigms in adult animals, including the open field test, elevated plus maze, nose‐poke assay, accelerating rotarod, social partition task, three‐chambered social task, and two different fear conditioning paradigms. Tests were ordered such that the most invasive tests were performed last in the sequence, and testing paradigms for similar behaviors were performed in separate cohorts to minimize testing effects.ResultsOur results indicate several sex‐specific changes in Fmr1 knockout mice, including male‐specific increases in activity levels, and female‐specific increases in repetitive behaviors on both the nose‐poke assay and motor coordination on the accelerating rotarod task. The results also indicated that Fmr1 deletion results in deficits in fear learning and memory across both sexes, and no changes in social behavior across two tasks.ConclusionThese findings highlight the importance of including female subjects in preclinical studies, as simply studying the impact of genetic mutations in males does not yield a complete picture of the phenotype. Further research should explore these marked phenotypic differences among the sexes. Moreover, given that treatment strategies are typically equivalent between the sexes, the results highlight a potential need for sex‐specific therapeutics.

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Section: Discussionmentioning

confidence: 99%

Deletion of Fmr1 results in sex‐specific changes in behavior

et al. 2017

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“…Additionally, Fmr1 KO mice buried more marbles in the marble burying test (93,107,124), a measure of repetitive behavior (134). However, marble burying was not significantly different between genotypes in some studies (91,110,135). Genotype differences in marble burying in Fmr1 KO mice appear to be dependent on background strain (107).…”

Section: Repetitive Behaviorsmentioning

confidence: 93%

“…Seizures associated with FXS are infrequent, are often partial, and are typically controlled with medications (82,83). Fmr1 KO mice have not been reported to display spontaneous seizures, but are more susceptible to audiogenic seizures, induced by exposure to a 125 decibel, high-intensity siren (48,81,(84)(85)(86)(87)(88)(89)(90)(91)(92)(93). Audiogenic seizure vulnerability in Fmr1 KO mice may reflect seizure susceptibly in FXS, although audiogenic seizure severity in Fmr1 KO mice varied in degree depending on age and background strain (86,91,94,95).…”

Section: Seizure and Stimuli Hypersensitivitymentioning

confidence: 99%

Modeling fragile X syndrome in the <i>Fmr1</i> knockout mouse

Kazdoba

Leach

Silverman

et al. 2014

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“…• 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%

“…Of note, recent studies in the mouse model showed that chronic treatment with mGlu5 NAMs is necessary to improve memory deficits [120,121,129], suggesting that prolonged treatment in patients may also be beneficial. Notably, targeting mGlu5 seems to be more efficient in rescuing phenotypes in the FXS mouse model than targeting other G-coupled receptors that were also shown to be dysregulated in FXS [217], such as mGlu1 or muscarinic receptors M1 and M4 [118,131,[136][137][138].…”

Section: Neurotransmitter Receptors Versus Intracellular Signaling Anmentioning

confidence: 99%

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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Modulation of behavioral phenotypes by a muscarinic M1 antagonist in a mouse model of fragile X syndrome

Abstract: Our findings suggest that pharmacologically reducing the activity through the mAChR M1 alters select behavioral responses in the Fmr1 KO mice.

Cited by 57 publications

References 50 publications

Deletion of Fmr1 results in sex‐specific changes in behavior

Deletion of Fmr1 results in sex‐specific changes in behavior

Modeling fragile X syndrome in the <i>Fmr1</i> knockout mouse

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

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