Modeling fragile X syndrome in the &lt;i&gt;Fmr1&lt;/i&gt; knockout mouse

Kazdoba, Tatiana M.; Leach, Prescott T.; Silverman, Jill L.; Crawley, Jacqueline N.

doi:10.5582/irdr.2014.01024

Cited by 188 publications

(171 citation statements)

References 212 publications

(247 reference statements)

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“…Nevertheless, the reduced locomotor activity observed in our study is difficult to reconcile with the hyperactivity generally associated with FXS patients (Hatton et al ., 2002; Sullivan et al ., 2006; Kazdoba et al ., 2014). Interestingly, hyperactivity in males with Fragile X has been shown to change over development with decreased activity in very young children followed by increase in preschoolers followed by decrease in adolescent boys (Tranfaglia 2011; Gabis et al ., 2011; Hustyi et al ., 2014).…”

Section: Discussionmentioning

confidence: 99%

“…These features include macroorchidism (Bakker et al ., 1994), hyperactivity (per open field test; Kazdoba et al ., 2014; also Mineur et al ., 2002), attention deficits (Moon et al ., 2006), altered anxiety-related behaviors (Kazdoba et al ., 2014; Saré et al ., 2016), impaired social communication (Mineur et al ., 2006), sensory filtering deficits (Frankland et al ., 2004), motor deficits (Padmashri et al ., 2013; Hodges et al ., in press), and subtle cognitive impairments (Bakker et al ., 1994). Further studies have replicated Fmr1 -KO subtle cognitive impairments (in water maze reversal task; D’Hooge et al ., 1997; radial arm task Mineur et al ., 2002; in fear memory Zhao et al ., 2005, in five-choice serial reaction time test, Krueger et al ., 2011).…”

Section: Introductionmentioning

confidence: 99%

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Decreased home cage movement and oromotor impairments in adult Fmr1‐KO mice

Bonasera

Chaudoin

Goulding

et al. 2017

Genes Brain and Behavior

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Fragile X syndrome (FXS) is a common inherited disorder that significantly impacts family and patient day-to-day living across the entire lifespan. The childhood and adolescent behavioral consequences of FXS are well-appreciated. However, there are significantly fewer studies (except those examining psychiatric comorbidities) assessing behavioral phenotypes seen in adults with FXS. Mice engineered with a genetic lesion of Fmr1 recapitulate important molecular and neuroanatomical characteristics of FXS, and provide a means to evaluate adult behavioral phenotypes associated with FXS. We give the first description of baseline behaviors including feeding, drinking, movement, and their circadian rhythms; all observed over 16 consecutive days following extensive environmental habituation in adult Fmr1-KO mutant mice. We find no genotypic changes in mouse food ingestion, feeding patterns, metabolism, or circadian patterns of movement, feeding, and drinking. After habituation, Fmr1-KO mice demonstrate significantly less daily movement during their active phase (the dark cycle). However, Fmr1-KO mice have more bouts of activity during the light cycle compared to wildtypes. In addition, Fmr1-KO mice demonstrate significantly less daily water ingestion during the circadian dark cycle, and this reduction in water intake is accompanied by a decrease in the amount of water ingested per lick. The observed water ingestion and circadian phenotypes noted in Fmr1-KO mice recapitulate known clinical aspects previously described in FXS. The finding of decreased movement in Fmr1-KO mice is novel, and suggests a dissociation between baseline and novelty-evoked activity for Fmr1-KO mice.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Decreased home cage movement and oromotor impairments in adult Fmr1‐KO mice

Bonasera

Chaudoin

Goulding

et al. 2017

Genes Brain and Behavior

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“…§ Patients with fragile X syndrome are intellectually impaired but direct correlates to these memory tests in rodents are, again, difficult to determine. 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%

“…Behavioral analyses of Fmr1 KO mice are mainly focused on autism-associated defects, for example perseverative behavior, anxiety, and impairments in social interaction (see Table 3; reviewed in [180]). Behavioral phenotypes of FXS mice vary considerably across laboratories, and even defects in the opposite directions have been reported frequently [179].…”

Section: Behavioral and Cognitive Phenotypes In The Fxs Mouse Modelmentioning

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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“…In terms of characteristics of a behavioral phenotype, sex is also a significant contributor to the clinical presentation of FXS, with male individuals showing more severe behavioral impairment as compared to females. Given that X‐linked disorders often follow a sex‐dependent pattern of symptom severity, this difference has been generally attributed to compensation by the second unaffected X chromosome in females (Germain, 2006; Kazdoba, Leach, Silverman, & Crawley, 2014). However, it has recently been hypothesized that the symptomatology of affected females may be qualitatively different than affected males.…”

Section: Introductionmentioning

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

Cited by 188 publications

References 212 publications

Decreased home cage movement and oromotor impairments in adult Fmr1‐KO mice

Decreased home cage movement and oromotor impairments in adult Fmr1‐KO mice

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

Deletion of Fmr1 results in sex‐specific changes in behavior

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