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Acquisition of Avoidance Responding in the Fmr1 Knockout Mouse  [PDF]
Maria G. Valdovinos, Kelly Ippolito, Lauren Nawrocki, Greg Woods
Psychology (PSYCH) , 2010, DOI: 10.4236/psych.2010.15045
Abstract: Fragile X Syndrome (FXS) is the most common inherited cause of mental retardation. Much work has been done characterizing the behavioral phenotype of the animal model of FXS, the Fmr1 knockout mouse. However, very little literature exists on knockout performance in the active avoidance task. This study evaluated if Fmr1 knockouts differed from wild type littermates in avoidance acquisition. Data revealed no difference in acquisition between knockouts and wild types.
Carriers of the fragile X mental retardation 1 (FMR1) premutation allele present with increased levels of cytokine IL-10  [cached]
Marek Diana,Papin Stephanie,Ellefsen Kim,Niederhauser Julien
Journal of Neuroinflammation , 2012, DOI: 10.1186/1742-2094-9-238
Abstract: Background Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited late-onset neurodegenerative disorder, characterized both by neurological and cognitive deficits. It is caused by the expansion of CGG repeats (55 to 200 repeats) in the noncoding region of the fragile X mental retardation 1 (FMR1) gene. Abnormal immunological patterns are often associated with neurodegenerative disorders and implicated in their etiology. We therefore investigated the immune status of FXTAS patients, which had not been assessed prior to this study. Method Peripheral blood mononuclear cells (PBMCs) were collected from 15 asymptomatic FMR1 premutation carriers and 20 age-matched controls. Concentrations of three cytokines (IL-6, IL-8, IL-10) were measured in PBMC supernatants using ELISA assays. Results We found a significant increase in the concentration of the major anti-inflammatory cytokine IL-10 in supernatants of PBMCs derived from premutation carriers, when compared with controls (P = 0.019). This increase correlated significantly with the number of CGG repeats (P = 0.002). Conclusions Elevated IL-10 levels were observed in all premutation carriers, before appearance of the classical neurological symptoms; therefore, IL-10 may be one of the early biomarkers of FXTAS.
Resilience to audiogenic seizures is associated with p-ERK1/2 dephosphorylation in the subiculum of Fmr1 knockout mice  [PDF]
Giulia Curia,Fabio Gualtieri,Regina Bartolomeo,Giuseppe Biagini
Frontiers in Cellular Neuroscience , 2013, DOI: 10.3389/fncel.2013.00046
Abstract: Young, but not adult, fragile X mental retardation gene (Fmr1) knockout (KO) mice display audiogenic seizures (AGS) that can be prevented by inhibiting extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation. In order to identify the cerebral regions involved in these phenomena, we characterized the response to AGS in Fmr1 KO mice and wild type (WT) controls at postnatal day (P) 45 and P90. To characterize the diverse response to AGS in various cerebral regions, we evaluated the activity markers FosB/ΔFosB and phosphorylated ERK1/2 (p-ERK1/2). Wild running (100% of tested mice) followed by clonic/tonic seizures (30%) were observed in P45 Fmr1 KO mice, but not in WT mice. In P90 Fmr1 KO mice, wild running was only present in 25% of tested animals. Basal FosB/ΔFosB immunoreactivity was higher (P < 0.01 vs. WT) in the CA1 and subiculum of P45 Fmr1 KO mice. Following the AGS test, FosB/ΔFosB expression consistently increased in most of the analyzed regions in both groups at P45, but not at P90. Interestingly, FosB/ΔFosB immunoreactivity was significantly higher in P45 Fmr1 KO mice in the medial geniculate body (P < 0.05 vs. WT) and CA3 (P < 0.01). Neurons presenting with immunopositivity to p-ERK1/2 were more abundant in the subiculum of Fmr1 KO mice in control condition (P < 0.05 vs. WT, in both age groups). In this region, p-ERK1/2-immunopositive cells significantly decreased (–75%, P < 0.01) in P90 Fmr1 KO mice exposed to the AGS test, but no changes were found in P45 mice or in other brain regions. In both age groups of WT mice, p-ERK1/2-immunopositive cells increased in the subiculum after exposure to the acoustic test. Our findings illustrate that FosB/ΔFosB markers are overexpressed in the medial geniculate body and CA3 in Fmr1 KO mice experiencing AGS, and that p-ERK1/2 is markedly decreased in the subiculum of Fmr1 KO mice resistant to AGS induction. These findings suggest that resilience to AGS is associated with dephosphorylation of p-ERK1/2 in the subiculum of mature Fmr1 KO mice.
Structure and stability upon maternal transmission of common and intermediate FMR1 (Fragile X Mental Retardation 1) alleles in a sample of the Brazilian population
Capelli, Leonardo P.;Mingroni-Netto, Regina C.;Vianna-Morgante, Angela M.;
Genetics and Molecular Biology , 2005, DOI: 10.1590/S1415-47572005000100002
Abstract: in order to investigate the stability of the fmr1 (fragile x mental retardation 1) alleles from the normal population, when maternally inherited, we analyzed 75 mother-to-son transmissions. sixty-eight alleles fell within the common range with 20-40 cgg repeats, and seven alleles were intermediate, with 41-48 repeats. no change was observed either in the length or in the structure of these repeats upon transmission. fifty-three alleles were ascertained in different families, and their size distribution was similar to those described for european and european-derived populations, with three peaks of frequency: 66% of the alleles with (cgg)29, (cgg)30 or (cgg)31, 7.5% with (cgg)20, and 5.7% with (cgg)23. regarding the agg interspersion pattern, 69.8% had two agg repeats, 20.8% had one, 5.7% had three and 3.8% had none. the most common patterns were 10+9+9 (30.2%), 9+9+9 (18.9%), 10+9 (7.5%), and 10+9+10 (7.5%). about 70% of the alleles with up to 40 repeats were linked to the dxs548/fraxac1 haplotype 7-3, the most commonly reported in normal populations. four out of five intermediate alleles were in linkage with the two haplotypes most frequently associated to the fmr1 full mutation, 2-1 and 6-4. these four alleles showed long uninterrupted cgg repeats at the 3' end. the 9+9+22, 9+9+23 and 9+9+28 alleles were linked to the haplotype 2-1, and the 9+37 allele, to the haplotype 6-4. the pattern of agg interspersion of these alleles and the associated haplotypes were in accordance with the two main pathways toward mutation previously proposed.
Behavioral and Synaptic Circuit Features in a Zebrafish Model of Fragile X Syndrome  [PDF]
Ming-Chong Ng, Yi-Ling Yang, Kwok-Tung Lu
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0051456
Abstract: Fragile X syndrome (FXS) is the most frequent inherited form of human mental retardation. It is characterized by cognitive impairment and physical and behavioral problems and is caused by the silencing of fmr1 transcription and the absence of the fmr1 protein (FMRP). Recently, animal models of FXS have greatly facilitated the investigation of the molecular and cellular mechanisms of this loss-of-function disorder. The present study was aimed to further characterize the role of FMRP in behavior and synaptic function by using fmr1 knockout zebrafish. In adult zebrafish, we found that fmr1 knockout produces the anxiolytic-like responses of increased exploratory behavior in light/dark and open-field tests and avoidance learning impairment. Furthermore, electrophysiological recordings from telencephalic slice preparations of knockout fish displayed markedly reduced long-term potentiation and enhanced long-term depression compared to wild-type fish; however, basal glutamatergic transmission and presynaptic function at the lateral (Dl) and medial (Dm) division of the dorsal telencephalon synapse remained normal. Taken together, our study not only evaluates the mechanism of FRMP but also suggests that zebrafish have valuable potential as a complementary vertebrate model in studying the molecular pathogenesis of human fragile X syndrome.
GSK3 Influences Social Preference and Anxiety-Related Behaviors during Social Interaction in a Mouse Model of Fragile X Syndrome and Autism  [PDF]
Marjelo A. Mines,Christopher J. Yuskaitis,Margaret K. King,Eleonore Beurel,Richard S. Jope
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0009706
Abstract: Nearly 1% of children in the United States exhibit autism spectrum disorders, but causes and treatments remain to be identified. Mice with deletion of the fragile X mental retardation 1 (Fmr1) gene are used to model autism because loss of Fmr1 gene function causes Fragile X Syndrome (FXS) and many people with FXS exhibit autistic-like behaviors. Glycogen synthase kinase-3 (GSK3) is hyperactive in brains of Fmr1 knockout mice, and inhibition of GSK3 by lithium administration ameliorates some behavioral impairment in these mice. We extended our studies of this association by testing whether GSK3 contributes to socialization behaviors. This used two mouse models with disrupted regulation of GSK3, Fmr1 knockout mice and GSK3 knockin mice, in which inhibitory serines of the two isoforms of GSK3, GSK3α and GSK3β, are mutated to alanines, leaving GSK3 fully active.
Generation and Characterization of Fmr1 Knockout Zebrafish  [PDF]
Marjo J. den Broeder,Herma van der Linde,Judith R. Brouwer,Ben A. Oostra,Rob Willemsen,René F. Ketting
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0007910
Abstract: Fragile X syndrome (FXS) is one of the most common known causes of inherited mental retardation. The gene mutated in FXS is named FMR1, and is well conserved from human to Drosophila. In order to generate a genetic tool to study FMR1 function during vertebrate development, we generated two mutant alleles of the fmr1 gene in zebrafish. Both alleles produce no detectable Fmr protein, and produce viable and fertile progeny with lack of obvious phenotypic features. This is in sharp contrast to published results based on morpholino mediated knock-down of fmr1, reporting defects in craniofacial development and neuronal branching in embryos. These phenotypes we specifically addressed in our knock-out animals, revealing no significant deviations from wild-type animals, suggesting that the published morpholino based fmr1 phenotypes are potential experimental artifacts. Therefore, their relation to fmr1 biology is questionable and morpholino induced fmr1 phenotypes should be avoided in screens for potential drugs suitable for the treatment of FXS. Importantly, a true genetic zebrafish model is now available which can be used to study FXS and to derive potential drugs for FXS treatment.
Comprehensive Analysis of Ultrasonic Vocalizations in a Mouse Model of Fragile X Syndrome Reveals Limited, Call Type Specific Deficits  [PDF]
Snigdha Roy,Nick Watkins,Detlef Heck
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044816
Abstract: Fragile X syndrome (FXS) is a well-recognized form of inherited mental retardation, caused by a mutation in the fragile X mental retardation 1 (Fmr1) gene. The gene is located on the long arm of the X chromosome and encodes fragile X mental retardation protein (FMRP). Absence of FMRP in fragile X patients as well as in Fmr1 knockout (KO) mice results, among other changes, in abnormal dendritic spine formation and altered synaptic plasticity in the neocortex and hippocampus. Clinical features of FXS include cognitive impairment, anxiety, abnormal social interaction, mental retardation, motor coordination and speech articulation deficits. Mouse pups generate ultrasonic vocalizations (USVs) when isolated from their mothers. Whether those social ultrasonic vocalizations are deficient in mouse models of FXS is unknown. Here we compared isolation-induced USVs generated by pups of Fmr1-KO mice with those of their wild type (WT) littermates. Though the total number of calls was not significantly different between genotypes, a detailed analysis of 10 different categories of calls revealed that loss of Fmr1 expression in mice causes limited and call-type specific deficits in ultrasonic vocalization: the carrier frequency of flat calls was higher, the percentage of downward calls was lower and that the frequency range of complex calls was wider in Fmr1-KO mice compared to their WT littermates.
The Cyclic AMP Cascade Is Altered in the Fragile X Nervous System  [PDF]
Daniel J. Kelley, Richard J. Davidson, Jamie L. Elliott, Garet P. Lahvis, Jerry C. P. Yin, Anita Bhattacharyya
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0000931
Abstract: Fragile X syndrome (FX), the most common heritable cause of mental retardation and autism, is a developmental disorder characterized by physical, cognitive, and behavioral deficits. FX results from a trinucleotide expansion mutation in the fmr1 gene that reduces levels of fragile X mental retardation protein (FMRP). Although research efforts have focused on FMRP's impact on mGluR signaling, how the loss of FMRP leads to the individual symptoms of FX is not known. Previous studies on human FX blood cells revealed alterations in the cyclic adenosine 3′, 5′-monophosphate (cAMP) cascade. We tested the hypothesis that cAMP signaling is altered in the FX nervous system using three different model systems. Induced levels of cAMP in platelets and in brains of fmr1 knockout mice are substantially reduced. Cyclic AMP induction is also significantly reduced in human FX neural cells. Furthermore, cAMP production is decreased in the heads of FX Drosophila and this defect can be rescued by reintroduction of the dfmr gene. Our results indicate that a robust defect in cAMP production in FX is conserved across species and suggest that cAMP metabolism may serve as a useful biomarker in the human disease population. Reduced cAMP induction has implications for the underlying causes of FX and autism spectrum disorders. Pharmacological agents known to modulate the cAMP cascade may be therapeutic in FX patients and can be tested in these models, thus supplementing current efforts centered on mGluR signaling.
Epigenetic Characterization of the FMR1 Gene and Aberrant Neurodevelopment in Human Induced Pluripotent Stem Cell Models of Fragile X Syndrome  [PDF]
Steven D. Sheridan, Kraig M. Theriault, Surya A. Reis, Fen Zhou, Jon M. Madison, Laurence Daheron, Jeanne F. Loring, Stephen J. Haggarty
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026203
Abstract: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. In addition to cognitive deficits, FXS patients exhibit hyperactivity, attention deficits, social difficulties, anxiety, and other autistic-like behaviors. FXS is caused by an expanded CGG trinucleotide repeat in the 5′ untranslated region of the Fragile X Mental Retardation (FMR1) gene leading to epigenetic silencing and loss of expression of the Fragile X Mental Retardation protein (FMRP). Despite the known relationship between FMR1 CGG repeat expansion and FMR1 silencing, the epigenetic modifications observed at the FMR1 locus, and the consequences of the loss of FMRP on human neurodevelopment and neuronal function remain poorly understood. To address these limitations, we report on the generation of induced pluripotent stem cell (iPSC) lines from multiple patients with FXS and the characterization of their differentiation into post-mitotic neurons and glia. We show that clones from reprogrammed FXS patient fibroblast lines exhibit variation with respect to the predominant CGG-repeat length in the FMR1 gene. In two cases, iPSC clones contained predominant CGG-repeat lengths shorter than measured in corresponding input population of fibroblasts. In another instance, reprogramming a mosaic patient having both normal and pre-mutation length CGG repeats resulted in genetically matched iPSC clonal lines differing in FMR1 promoter CpG methylation and FMRP expression. Using this panel of patient-specific, FXS iPSC models, we demonstrate aberrant neuronal differentiation from FXS iPSCs that is directly correlated with epigenetic modification of the FMR1 gene and a loss of FMRP expression. Overall, these findings provide evidence for a key role for FMRP early in human neurodevelopment prior to synaptogenesis and have implications for modeling of FXS using iPSC technology. By revealing disease-associated cellular phenotypes in human neurons, these iPSC models will aid in the discovery of novel therapeutics for FXS and other autism-spectrum disorders sharing common pathophysiology.
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