FMR1基因敲除鼠感觉皮质功能柱树突棘修剪发育的研究

目的研究脆性X智力低下蛋白（FMRP）缺失对感觉皮质功能柱神经可塑性的影响。方法从纯合子鼠血液提取DNA，对FMR1基因片段进行扩增，电泳观察结果。并选用子代幼龄FMR1基因敲除及野生型小鼠共16只，按基因型和年龄分为1周龄FMR1基因敲除型组（KO^1），1周龄野生型组（WT^1），4周龄FMR1基因敲除型组（KO^4），4周龄野生型组（WT^4），每组各4只。采用快速Golgi染色法分别观察不同发育时间段感觉皮质功能柱区域神经元的功能柱中心和周边两个方向上树突分支、树突棘密度和长度。结果与对照组相比，幼龄FMR1基因敲除鼠树突棘密度显著增高（P〈0．05）而长度无变化，感觉皮质功能柱区域中心朝向的树突棘密度无显著性差异，而周边朝向的树突棘密度KO^1、KO^4分别高于WT^1、WT^4，并且主要表现在距胞体10～80μm段的密度异常（P〈0．01）。结论FMRP缺失导致树突棘密度增高和感觉皮质功能柱区域树突棘修剪异常，并且树突棘修剪和树突修剪的机制不同。     

Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome

Carriers of the fragile X premutation (FPM) have CGG trinucleotide repeat expansions of between 55 and 200 in the 5′-UTR of FMR1, compared to a CGG repeat length of between 5 and 54 for the general population. Carriers were once thought to be without symptoms, but it is now recognized that they can develop a variety of early neurological symptoms as well as being at risk for developing the late onset neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Several mouse models have contributed to our understanding of FPM and FXTAS, and findings from studies using these models are summarized here. This review also discusses how this information is improving our understanding of the molecular and cellular abnormalities that contribute to neurobehavioral features seen in some FPM carriers and in patients with FXTAS. Mouse models show much of the pathology seen in FPM carriers and in individuals with FXTAS, including the presence of elevated levels of Fmr1 mRNA, decreased levels of fragile X mental retardation protein, and ubiquitin-positive intranuclear inclusions. Abnormalities in dendritic spine morphology in several brain regions are associated with neurocognitive deficits in spatial and temporal memory processes, impaired motor performance, and altered anxiety. In vitro studies have identified altered dendritic and synaptic architecture associated with abnormal Ca²⁺ dynamics and electrical network activity. FPM mice have been particularly useful in understanding the roles of Fmr1 mRNA, fragile X mental retardation protein, and translation of a potentially toxic polyglycine peptide in pathology. Finally, the potential for using these and emerging mouse models for preclinical development of therapies to improve neurological function in FXTAS is considered.     

Audiogenic seizure susceptibility is reduced in fragile X knockout mice after introduction of FMR1 transgenes

The Fmr1 knockout (KO) mouse is characterized by an increased audiogenic seizure (AGS) susceptibility and is considered a good animal model for epilepsy and seizures in the human fragile-X (FRAX) syndrome. Here, we tested the hypothesis that the reintroduction of the FMR1 gene is able to revert the AGS susceptibility characterizing Fmr1 KO mice. To this aim, two groups of Fmr1 KO transgenic mice, which have additional copies of the human FMR1 gene (YAC) or FMR1 cDNA (G6) were used. AGS susceptibility of these mice was examined and compared to that of Fmr1 KO, wild type, and wild-type animals in whom the FMR1gene was also introduced (over-expressed). Mice were tested at different ages because AGS susceptibility is age dependent. The intensity of response was scored and the results were analyzed by means of 2-way analysis of variance to evaluate the effects of age and genetic condition. We found that AGS susceptibility rescue is complete in the G6 mice and partial in YAC mice. Our data indicate that the introduction of the human FMR1 gene in Fmr1 KO mice is able to revert the Fmr1 KO epileptic phenotype.     

Decreased expression of the GABAA receptor in fragile X syndrome

After our initial discovery of under expression of the GABA(A) receptor delta subunit in a genome wide screening for differentially expressed mRNAs in brain of fragile X mice, a validated model for fragile X mental retardation syndrome, we analyzed expression of the 17 remaining subunits of the GABA(A) receptor using real-time PCR. We confirmed nearly 50% under expression of the delta subunit and found a significant 35%-50% reduction in expression of 7 additional subunit mRNAs, namely alpha(1), alpha(3), and alpha(4), beta(1) and beta(2) and gamma(1) and gamma(2), in fragile X mice compared to wild-type littermates. In concordance with previous results, under expression was found in cortex, but not in cerebellum. Moreover, decreased expression of specific GABA(A) receptor subunits in fragile X syndrome seems to be an evolutionary conserved hallmark since in the fragile X fly (Drosophila melanogaster) model we also found almost 50% under expression of all 3 subunits which make up the invertebrate GABA receptor, namely Grd, Rdl and Lcch3. In addition, we demonstrated a direct correlation between the amount of dFmrp and the expression of the GABA receptor subunits Rdl and Grd. Our results add evidence to previous observations of an altered GABAergic system in fragile X syndrome. Because GABA(A) receptors are the major inhibitory receptors in brain, involved in anxiety, depression, insomnia, learning and memory and epilepsy, processes also disturbed in fragile X patients, the well described GABA(A) receptor pharmacology might open new powerful opportunities for treatment of the behavioral and epileptic phenotype associated with fragile X syndrome.     

Unaltered hormonal response to stress in a mouse model of fragile X syndrome

Reports in the clinical literature and studies of fmr1 knockout mice have led to the hypothesis that, in addition to mental retardation, fragile X syndrome is characterized by a dysregulation of hypothalamic-pituitary-adrenal axis function. We have systematically examined this hypothesis by studying the effects of stress on adrenocorticotrophic hormone and corticosterone levels in adult, male fmr1 knockout mice. Initially we determined the circadian rhythms of the plasma hormone levels in both wild-type and fmr1 knockout mice and established the optimal time to impose the stress. We found no genotypic differences in the circadian rhythms of either hormone. We studied two types of stressors, immobilization and spatial novelty; spatial novelty was 5min in an elevated plus-maze. We varied the duration of immobilization and followed the time course of recovery of hormones to their pre-stress levels. Despite the lower anxiety exhibited by fmr1 knockout mice in the elevated plus-maze, hormonal responses to and recovery from this spatial novelty were similar in both genotypes. Further, we found no genotypic differences in hormonal responses to immobilization stress. The results of our study indicate that, in FVB/NJ mice, the hormonal response to and recovery from acute stress is unaltered by the lack of fragile X mental retardation protein.     

Corticosterone response to acute stress in a mouse model of Fragile X syndrome

Fragile X syndrome (FXS), the most common form of inherited mental retardation, results from the silencing of the Fmr1 gene that encodes the Fragile X mental retardation protein (FMRP). Because (1) mRNA for the glucocorticoid receptor is bound by FMRP and (2) the response to acute stress is elevated in children with FXS, we examined whether this heightened response is characteristic of a mouse model of FXS. Fmr1 knockout (KO) and wildtype (WT) control mice were exposed to 30 min of acute restraint; serum corticosterone levels were assayed from unstressed animals and those examined either immediately following stress or after a 15 or 60 min recovery period. Under unstressed conditions, KOs and WTs did not differ in serum corticosterone, although both genotype and sex affected corticosterone levels observed following exposure to acute stress. Similar to FXS patients, serum glucocorticoid levels of KO mice exhibited a protracted return to baseline following acute stress. This suggests that the stress response is misregulated in Fmr1 KO mice as in FXS patients and provides the first evidence for a link between a particular FMRP-binding mRNA and a functional phenotype of FXS (impaired glucocorticoid negative feedback).     

Genetic reduction of group 1 metabotropic glutamate receptors alters select behaviors in a mouse model for fragile X syndrome

Introduction

Genetic heterogeneity likely contributes to variability in the symptoms among individuals with fragile X syndrome (FXS). Studies in the Fmr1 knockout (KO) mouse model for FXS suggest that excessive signaling through group I metabotropic glutamate receptors (Gp1 mGluRs), comprised of subtypes mGluR1 and mGluR5, may play a role. Hence, Gp1 mGluRs may act as modifiers of FXS. Currently no studies have addressed whether manipulation of mGluR1 activity may alter Fmr1 KO behavioral responses, and only a few have reported the effects of mGluR5 manipulation. Therefore, the goals for this study were to extend our understanding of the effects of modulating Gp1 mGluR activity on Fmr1 KO behavioral responses.

Methods

The present study determined if genetically reducing mGluR1 or mGluR5 by 50% affects an extensive array of behaviors in the Fmr1 KO.

Results

Reduction of mGluR1 moderately decreased Fmr1 KO activity. Reduction of mGluR5 caused an analgesic response in the Fmr1 KO and decreased active social behavior. Modulation of either mGluR1 or mGluR5 did not significantly alter audiogenic seizures, anxiety- and perseverative-related responses, sensorimotor gating, memory, or motor responses.

Conclusions

Genetic reduction of mGluR1 or mGluR5 modified a few select Fmr1 KO behaviors, although these modifications appeared to be subtle in nature and/or limited to select behaviors. This may indicate that 50% reduction of either mGluR1 or mGluR5 is insufficient to produce behavioral changes, and therefore, these receptors may not be dominant modifiers of a number of Fmr1 KO behavioral phenotypes.     

Drebrins和Icam-5在Fmr-1基因敲除鼠大脑皮层的表达和意义

目的 观察脆性X综合征(FXS)模型小鼠不同发育时期大脑皮层中Drebrin A、Drebrin E及Icam-5 mRNA水平变化情况及意义.方法 应用荧光实时定量PCR(RT-PCR)法检测FmrJ基因敲除KO小鼠及野生健康对照小鼠H出生后第7天、第14天、第21天和第28天大脑皮层Drebrin A、Drebrin E及Icam-5 mRNA的表达(4≤n≤10).结果 KO组小鼠出生后第14天Drebrin A mRNA水平较健康对照组小鼠明显降低,而同时间Drebrin E mRNA水平较健康对照组小鼠明显增高,差异均有统计学意义(P＜0.05);KO组小鼠Icam-5 mRNA水平在出生后第14和21天均明显高于健康对照组,差异均有统计学意义(P＜0.05).结论 Drebrin A和Drebrin E在大脑皮层发育期的表达交替延迟及Icam-5的一过性过度表达是FXS智力低下的原因之一.     

An fMRI study of the prefrontal activity during the performance of a working memory task in premutation carriers of the fragile X mental retardation 1 gene with and without fragile X-associated tremor/ataxia syndrome (FXTAS)

Premutation alleles of the fragile X mental retardation 1 gene (FMR1) are associated with the risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder that involves neuropsychiatric problems and executive and memory deficits. Although abnormal elevation of FMR1 mRNA has been proposed to underlie these deficits, it remains unknown which brain regions are affected by the disease process of FXTAS and genetic molecular mechanisms associated with the FMR1 premutation. This study used functional magnetic resonance imaging (fMRI) to identify deficient neural substrates responsible for altered executive and memory functions in some FMR1 premutation individuals. We measured fMRI BOLD signals during the performance of verbal working memory from 15 premutation carriers affected by FXTAS (PFX+), 15 premutation carriers unaffected by FXTAS (PFX−), and 12 matched healthy control individuals (HC). We also examined correlation between brain activation and FMR1 molecular variables (CGG repeat size and mRNA levels) in premutation carriers. Compared with HC, PFX+ and PFX− showed reduced activation in the right ventral inferior frontal cortex and left premotor/dorsal inferior frontal cortex. Reduced activation specific to PFX+ was found in the right premotor/dorsal inferior frontal cortex. Regression analysis combining the two premutation groups demonstrated significant negative correlation between the right ventral inferior frontal cortex activity and the levels of FMR1 mRNA after excluding the effect of disease severity of FXTAS. These results indicate altered prefrontal cortex activity that may underline executive and memory deficits affecting some individuals with FMR1 premutation including FXTAS patients.     

Age-dependent cognitive changes in carriers of the fragile X syndrome

Fragile X syndrome is a neurodevelopmental disorder that is caused by the silencing of a single gene on the X chromosome, the fragile X mental retardation 1 (FMR1) gene. Affected individuals display a unique neurocognitive phenotype that includes significant impairment in inhibitory control, selective attention, working memory, and visual–spatial cognition. In contrast, little is known about the trajectory and specificity of any cognitive impairment associated with the fragile X premutation (i.e., “carrier status”) or its relationship with the recently identified neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). In the present study, we evaluated a broad sample of 40 premutation males (PM) aged 18–69 years matched on age and IQ to 67 unaffected comparison males (NC). Performance was compared across a range of cognitive domains known to be impaired in fragile X syndrome (i.e., “full mutation”). Tremor was also assessed using a self-report neurological questionnaire. PM displayed statistically significant deficits in their ability to inhibit prepotent responses, differentiating them from NC from age 30 onwards. With increasing age, the two groups follow different trajectories, with PM developing progressively more severe problems in inhibitory control. This deficit also has a strong co-occurrence in males displaying FXTAS-related symptomatology (p < .001). Selective attention was also impaired in PM but did not show any disproportionate aging effect. No other cognitive deficits were observed. We conclude that an inhibitory deficit and its impact across the lifespan are specifically associated with the fragile X premutation status, and may be a precursor for development of a more severe form of cognitive impairment or dementia, which has been reported in patients with the diagnosis of FXTAS.     

Treatment effects of stimulant medication in young boys with fragile X syndrome

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and is caused by a CGG repeat expansion at Xq27.3 on the FMR1 gene. The majority of young boys with FXS display poor attention and hyperactivity that is disproportionate to their cognitive disability, and approximately 70% meet diagnostic criteria for attention-deficit/hyperactivity disorder. Psychopharmacology is employed with 82% of young males 5–17 years of age, with stimulant medication as the most common medication prescribed. This study evaluated the effects of stimulant medication on the academic performance, attention, motor activity, and psychophysiological arousal of boys with FXS, as well as the concordance of effects within individuals. Participants in this study included 12 boys with FXS who were treated with stimulants. Participants completed videotaped academic testing on two consecutive days and were randomly assigned to be off stimulants for 1 day and on stimulants the other day. On each day, multiple measures including academic performance, behavior regulation, and psychophysiological arousal were collected. Approximately 75% of participants performed better on attention and academic measures, and 70% showed improved physiological regulation while on stimulant medication. A high degree of concordance among measures was found. Lower intelligence quotient (IQ), but not age, correlated with greater improvements in in-seat behavior. IQ and age did not relate to on-task behaviors. The frequency and magnitude of response to stimulant medication in boys with FXS is higher than those reported for most children with non-specific intellectual disabilities and autism spectrum disorder.     

Cellular distribution of the fragile X mental retardation protein in the mouse brain

The fragile X mental retardation protein (FMRP) plays an important role in normal brain development. Absence of FMRP results in abnormal neuronal morphologies in a selected manner throughout the brain, leading to intellectual deficits and sensory dysfunction in the fragile X syndrome (FXS). Despite FMRP importance for proper brain function, its overall expression pattern in the mammalian brain at the resolution of individual neuronal cell groups is not known. In this study we used FMR1 knockout and isogenic wildtype mice to systematically map the distribution of FMRP expression in the entire mouse brain. Using immunocytochemistry and cellular quantification analyses, we identified a large number of prominent cell groups expressing high levels of FMRP at the subcortical levels, in particular sensory and motor neurons in the brainstem and thalamus. In contrast, many cell groups in the midbrain and hypothalamus exhibit low FMRP levels. More important, we describe differential patterns of FMRP distribution in both cortical and subcortical brain regions. Almost all major brain areas contain high and low levels of FMRP cell groups adjacent to each other or between layers of the same cortical areas. These differential patterns indicate that FMRP expression appears to be specific to individual neuronal cell groups instead of being associated with all neurons in distinct brain regions, as previously considered. Taken together, these findings support the notion of FMRP differential neuronal regulation and strongly implicate the contribution of fundamental sensory and motor processing at subcortical levels to FXS pathology. J. Comp. Neurol. 525:818–849, 2017. © 2016 Wiley Periodicals, Inc.     

Genetic reduction of muscarinic M4 receptor modulates analgesic response and acoustic startle response in a mouse model of fragile X syndrome (FXS)

Introduction

The G-protein coupled muscarinic acetylcholine receptors, widely expressed in the CNS, have been implicated in fragile X syndrome (FXS). Recent studies have reported an overactive signaling through the muscarinic receptors in the Fmr1KO mouse model. Hence, it was hypothesized that reducing muscarinic signaling might modulate behavioral phenotypes in the Fmr1KO mice. Pharmacological studies from our lab have provided evidence for this hypothesis, with subtype-preferring muscarinic M₁ and M₄ receptor antagonists modulating select behaviors in the Fmr1KO mice. Since the pharmacological antagonists were not highly specific, we investigated the specific role of M₄ receptors in the Fmr1KO mouse model, using a genetic approach.

Methods

We created a double mutant heterozygous for the M₄ receptor gene and hemizygous for the Fmr1 gene and examined the mutants on various behaviors. Each animal was tested on a behavior battery comprising of open-field activity (activity), light-dark (anxiety), marble burying (perseverative behavior), prepulse inhibition (sensorimotor gating), rotarod (motor coordination), passive avoidance (learning and memory) and hotplate (analgesia). Animals were also tested on the audiogenic seizure protocol and testis weights were measured.

Results

Reduction of M₄ receptor expression in the heterozygotes completely rescued the analgesic response and partly rescued the acoustic startle response phenotype in the Fmr1KO mice. However, no modulation was observed in a number of behaviors including learning and memory, activity, perseverative behavior and audiogenic seizures.

Conclusion

Reducing M₄ receptor signaling altered only select behavioral phenotypes in the Fmr1KO mouse model, suggesting that other targets are involved in the modulation of fragile X behaviors.     

Insular volume reduction in fragile X syndrome

Fragile X syndrome (FraX) is the most common form of inherited mental deficit and is caused by mutations of the Fragile X Mental Retardation 1 (FMR1) gene on the X chromosome. While males and females with the full FMR1 mutation are affected differently because the disorder is X-linked, both suffer from varying degrees of cognitive impairment, attention deficits and social anxiety. The insula is a sensory integrative region that has been increasingly suggested as a critical area involved in anxiety manifestation.The current study was designed to examine possible changes in insular volume in FraX compared to age- and gender-matched typically developing healthy controls (HC) as well as age-, gender-, and intelligence-matched developmentally delayed controls (DD). An established native-space, manual morphometry method was utilized to quantify total and regional insular volumes using structural magnetic resonance imaging.Total, anterior and posterior insular volumes were found to be reduced in FraX compared to both HC and DD. The current data add to a growing literature concerning brain abnormalities in FraX and suggests that significant volume reduction of the insula is a component of the FraX neuroanatomical phenotype. This finding also provides an intriguing potential neural correlate for hyperarousal and gaze aversion, which are prominent behavioral symptoms of FraX.     

Altered anxiety and social behaviors in a mouse model of Fragile X syndrome treated with hyperbaric oxygen therapy

Fragile X syndrome (FXS) is a common mental retardation syndrome. Anxiety and abnormal social behaviors are prominent features of FXS in humans. To better understand the effects of hyperbaric oxygen therapy (HBOT) on these behaviors, we analyzed anxiety-related and social behaviors in Fmr1 knockout mice treated by HBOT. In the open field test, HBOT group mice preferred the periphery to central areas and tended to run or walk along the wall. The results suggested that thigmotaxis was significantly increased in the HBOT group compared with the control group. In the elevated plus maze test, the percentage of distance traveled was significantly increased in the open arm and significantly decreased in the closed arm for HBOT group mice compared with control group mice. These results suggested that HBOT group mice displayed enhanced motor activity in the open arm and exhibited fewer anxiety-related behaviors. In the three-chambered social approach test, the HBOT group mice made more approaches to the wire cup containing an acquaintance mouse than control group mice in the sociability test and made more approaches to the wire cup containing a stranger mouse than control group mice in the social novelty preference test. The results suggested that HBOT group mice showed increased levels of social interaction and decreased “social anxiety” than the control group to partner mice in this test. Our findings indicated that HBOT resulted in altered anxiety and social behavior in Fmr1 knockout mice and could possibly be used as a treatment for FXS.     

LIMK1mRNA及其蛋白在脆性X综合征小鼠大脑皮层中的表达

目的 观察LIMK1 mRNA及其蛋白在脆性X综合征(FXS)小鼠大脑皮层中的表达,探讨其在FXS发病机制中的作用.方法 选择雄性FMR1基因敲除型FVB近交系新生鼠和2、4、6周小鼠做为实验组(记为 KO0d、KO2W、KO4W和KO6W),雄性同龄野生小鼠(WT)作为对照组(记为WT0d、WT2W、WT4W和WT6W),每组每时间点9只.取小鼠单侧大脑皮层行LIMK1 mRNA实时荧光定量PCR分析,取另一侧大脑皮层行LIMK1蛋白Western blotting分析.结果 (1)KO6W组小鼠LIMK1 mRNA含量较同龄组WT小鼠及KO0d、KO2W和KO4W组小鼠明显升高,WT0d组小鼠LIMK1mRNA含量明显高于WT2W、WT4W和WT6W组小鼠,差异有统计学意义(P<0.05).(2)同龄KO、WT小鼠大脑皮层中LIMK1蛋白含量差异无统计学意义(P>0.05);KO0d组小鼠LIMK1蛋白含量明显低于KO2W、KO4W和KO6W组,WT0d组小鼠大脑皮层中LIMK1蛋白含量明显低于WT2W、WT4W和WT6W组,差异有统计学意义(P<0.05).结论 LIMK1蛋白的翻译过程在6周时受到明显抑制,反馈性调节转录过程使LIMK1 mRNA表达急剧升高.KO鼠LIMK1蛋白表达下降,从而影响树突棘的骨架蛋白重构,影响树突棘的功能改变,可能是FXS神经系统改变的重要机制之一.

Abstract：

Objective To observe the mRNA and protein expressions of LIMK1 in the cerebral cortex of mice with FMR1 gene knockout, and explore the roles of LIMK1 mRNA and LIMK1 protein inthe pathogenic mechanism of fragile X syndrome (FXS). Methods FVB strain male mice with FMR1 gene knockout (KO, n=36, experimental group) and their wild type (WT, n=36, control group) were equally divided into 8 counterpart subgroups (WT0d, WT2W, WT4W, WT6W, KO0d, KO2W, KO4W and KO6W),respectively, according to different ages. LIMK1 mRNA expression in the left sides of the cerebral cortex were analyzed with RT-qPCR and protein expression of LIMK1 in another side with Western blotting.Results No significant differences of LIMK1 mRNA expression in the cerebral cortex of KO0d, KO2Wand KO4W subgroups were noted as compared with that of respective age-matched WT mice (P>0.05);but that of KO6W subgroup was significantly increased as compared with that of WT6W subgroup, and KO0d,KO2W and KO4W subgroups (P<0.05);the level of LIMK1 mRNA in WT0d subgroup was obviously higher than that of WT2W, WT4W and WT6W subgroups (P<0.05). No statistic differences of LIMK1 protein between the same-age KO and WT mice were noted (P>0.05);significantly lower level of LIMK1 protein in KO0d subgroup was found as compared with that of KO2W, KO4W and KO6W subgroups (P<0.05);that of WT0d subgroup was lower than that of WT2W, WT4W and WT6W subgroups (P<0.05). Conclusion The translation process of LIMK1 protein is significantly inhibited at 6 weeks and LIMK1 mRNA expression increased sharply based on the feedback adjustment of LIMK1 protein expression declining;once this translation process is inhibited or interrupted, it will affect the dendritic spines skeleton protein reconstruct and lead to the dendritic spines function deficient;the inhabitation of translation process might probably play an important role in the process of dendritic spines maturation and should be an important pathogenic mechanism of FXS.     

Alterations in the auditory startle response in Fmr1 targeted mutant mouse models of fragile X syndrome

Fragile X syndrome results from inadequate production of the fragile X mental retardation protein (FMRP). Mice with a mutation targeted to the Fmr1 gene lack FMRP and thus are a valuable animal model for studying the behavioral and neural phenotype of this human disorder. Mice of two genetic backgrounds containing the Fmr1 mutation, C57BL/6J (C57-KO) and an F1 hybrid (C57BL/6J mutant x FVB/NJ; F1-KO) did not differ from control mice in behavior in the elevated plus maze or the open field. Both the C57-KO and F1-KO mice exhibited greater startle responses than normal mice to low intensity (80 dB) white noise bursts and decreased responses to high intensity (120 dB) white noise bursts. These behavioral alterations appear to be specific to the Fmr1 mutation since they are present on both genetic backgrounds. Furthermore, the mice lacking FMRP resemble individuals with fragile X syndrome in their increased sensitivity to low intensity auditory stimuli. These findings should prove useful in determining how the absence of FMRP alters the brain and behavior, and in testing potential treatments for fragile X syndrome.     

A solution to limitations of cognitive testing in children with intellectual disabilities: the case of fragile X syndrome

Intelligence testing in children with intellectual disabilities (ID) has significant limitations. The normative samples of widely used intelligence tests, such as the Wechsler Intelligence Scales, rarely include an adequate number of subjects with ID needed to provide sensitive measurement in the very low ability range, and they are highly subject to floor effects. The IQ measurement problems in these children prevent characterization of strengths and weaknesses, poorer estimates of cognitive abilities in research applications, and in clinical settings, limited utility for assessment, prognosis estimation, and planning intervention. Here, we examined the sensitivity of the Wechsler Intelligence Scale for Children (WISC-III) in a large sample of children with fragile X syndrome (FXS), the most common cause of inherited ID. The WISC-III was administered to 217 children with FXS (age 6–17 years, 83 girls and 134 boys). Using raw norms data obtained with permission from the Psychological Corporation, we calculated normalized scores representing each participant’s actual deviation from the standardization sample using a z-score transformation. To validate this approach, we compared correlations between the new normalized scores versus the usual standard scores with a measure of adaptive behavior (Vineland Adaptive Behavior Scales) and with a genetic measure specific to FXS (FMR1 protein or FMRP). The distribution of WISC-III standard scores showed significant skewing with floor effects in a high proportion of participants, especially males (64.9%–94.0% across subtests). With the z-score normalization, the flooring problems were eliminated and scores were normally distributed. Furthermore, we found correlations between cognitive performance and adaptive behavior, and between cognition and FMRP that were very much improved when using these normalized scores in contrast to the usual standardized scores. The results of this study show that meaningful variation in intellectual ability in children with FXS, and probably other populations of children with neurodevelopmental disorders, is obscured by the usual translation of raw scores into standardized scores. A method of raw score transformation may improve the characterization of cognitive functioning in ID populations, especially for research applications.     

A cross-sectional analysis of orienting of visuospatial attention in child and adult carriers of the fragile X premutation

Background

Fragile X premutation carriers (fXPCs) have an expansion of 55–200 CGG repeats in the FMR1 gene. Male fXPCs are at risk for developing a neurodegenerative motor disorder (fragile X-associated tremor/ataxia syndrome (FXTAS)) often accompanied by cognitive decline. Several broad domains are implicated as core systems of dysfunction in fXPCs, including perceptual processing of spatial information, orienting of attention to space, and inhibiting attention to irrelevant distractors. We tested whether orienting of spatial attention is impaired in fXPCs.

Methods

Participants were fXPCs or healthy controls (HCs) asymptomatic for FXTAS. In experiment 1, they were male and female children and adults (aged 7–45 years). They oriented attention in response to volitional (endogenous) and reflexive (exogenous) cues. In experiment 2, the participants were men (aged 18–48 years). They oriented attention in an endogenous cueing task that manipulated the amount of information in the cue.

Results

In women, fXPCs exhibited slower reaction times than HCs in both the endogenous and exogenous conditions. In men, fXPCs exhibited slower reaction times than HCs in the exogenous condition and in the challenging endogenous cueing task with probabilistic cues. In children, fXPCs did not differ from HCs.

Conclusions

Because adult fXPCs were slower even when controlling for psychomotor speed, results support the interpretation that a core dysfunction in fXPCs is the allocation of spatial attention, while perceptual processing and attention orienting are intact. These findings indicate the importance of considering age and sex when interpreting and generalizing studies of fXPCs.