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https://www.readbyqxmd.com/read/29775702/abnormal-sleep-architecture-and-hippocampal-circuit-dysfunction-in-a-mouse-model-of-fragile-x-syndrome
#1
Christine E Boone, Heydar Davoudi, Jon B Harrold, David J Foster
Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and single-gene cause of autism spectrum disorder. The Fmr1 null mouse models much of the human disease including hyperarousal, sensory hypersensitivity, seizure activity, and hippocampus-dependent cognitive impairment. Sleep architecture is disorganized in FXS patients, but has not been examined in Fmr1 knockout (Fmr1-KO) mice. Hippocampal neural activity during sleep, which is implicated in memory processing, also remains uninvestigated in Fmr1-KO mice...
May 15, 2018: Neuroscience
https://www.readbyqxmd.com/read/29771335/loss-of-fragile-x-protein-fmrp-impairs-homeostatic-synaptic-downscaling-through-tumor-suppressor-p53-and-ubiquitin-e3-ligase-nedd4-2
#2
Kwan Young Lee, Kathryn A Jewett, Hee Jung Chung, Nien-Pei Tsai
Synaptic scaling allows neurons to homeostatically readjust synaptic strength upon chronic neural activity perturbations. Although altered synaptic scaling has been implicated to underlie imbalanced brain excitability in neurological disorders such as autism spectrum disorders and epilepsy, the molecular dysregulation and restoration of synaptic scaling in those diseases have not been demonstrated. Here, we showed that the homeostatic synaptic downscaling is absent in the hippocampal neurons of Fmr1 KO mice, the mouse model of the most common inherited autism, Fragile X Syndrome (FXS)...
May 16, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29766042/bc-rna-mislocalization-in-the-fragile-x-premutation
#3
Ilham A Muslimov, Taesun Eom, Anna Iacoangeli, Shih-Chieh Chuang, Renate K Hukema, Rob Willemsen, Dimitre G Stefanov, Robert K S Wong, Henri Tiedge
Fragile X premutation disorder is caused by CGG triplet repeat expansions in the 5' untranslated region of FMR1 mRNA. The question of how expanded CGG repeats cause disease is a subject of continuing debate. Our work indicates that CGG-repeat structures compete with regulatory BC1 RNA for access to RNA transport factor hnRNP A2. As a result, BC1 RNA is mislocalized in vivo, as its synapto-dendritic presence is severely diminished in brains of CGG-repeat knock-in animals (a premutation mouse model). Lack of BC1 RNA is known to cause seizure activity and cognitive dysfunction...
March 2018: ENeuro
https://www.readbyqxmd.com/read/29715444/dynamic-duo-fmrp-and-tdp-43-regulating-common-targets-causing-different-diseases
#4
Diana Ferro, Stephen Yao, Daniela C Zarnescu
RNA binding proteins play essential roles during development and aging, and are also involved in disease pathomechanisms. RNA sequencing and omics analyses have provided a window into systems level alterations in neurological disease, and have identified RNA processing defects among notable disease mechanisms. This review focuses on two seemingly distinct neurological disorders, the RNA binding proteins they are linked to, and their newly discovered functional relationship. When deficient, Fragile X Mental Retardation Protein (FMRP) causes developmental deficits and autistic behaviors while TAR-DNA Binding Protein (TDP-43) dysregulation causes age dependent neuronal degeneration...
April 28, 2018: Brain Research
https://www.readbyqxmd.com/read/29706865/mental-illnesses-associated-fxr1-and-its-negative-regulator-gsk3%C3%AE-are-modulators-of-anxiety-and-glutamatergic-neurotransmission
#5
Jivan Khlghatyan, Alesya Evstratova, Simon Chamberland, Aleksandra Marakhovskaia, Arash Bahremand, Katalin Toth, Jean-Martin Beaulieu
Genetic variants of the fragile X mental retardation syndrome-related protein 1 ( FXR1) have been associated to mood regulation, schizophrenia, and bipolar disorders. Nonetheless, genetic association does not indicate a functional link of a given gene to neuronal activity and associated behaviors. In addition, interaction between multiple genes is often needed to sculpt complex traits such as behavior. Thus, modulation of neuronal functions by a given gene product, such as Fxr1, has to be thoroughly studied in the context of its interactions with other gene products...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29704597/modelling-fragile-x-syndrome-in-the-laboratory-setting-a-behavioral-perspective
#6
REVIEW
Francesca Melancia, Viviana Trezza
Fragile X syndrome is the most common form of inherited mental retardation and the most frequent monogenic cause of syndromic autism spectrum disorders. The syndrome is caused by the loss of the Fragile X Mental Retardation Protein (FMRP), a key RNA-binding protein involved in synaptic plasticity and neuronal morphology. Patients show intellectual disability, social deficits, repetitive behaviors and impairments in social communication. The aim of this review is to outline the importance of behavioral phenotyping of animal models of FXS from a developmental perspective, by showing how the behavioral characteristics of FXS at the clinical level can be translated into effective, developmentally-specific and clinically meaningful behavioral readouts in the laboratory setting...
April 25, 2018: Behavioural Brain Research
https://www.readbyqxmd.com/read/29703945/critical-period-inhibition-of-nkcc1-rectifies-synapse-plasticity-in-the-somatosensory-cortex-and-restores-adult-tactile-response-maps-in-fragile-x-mice
#7
Qionger He, Erica D Arroyo, Samuel N Smukowski, Jian Xu, Claire Piochon, Jeffrey N Savas, Carlos Portera-Cailliau, Anis Contractor
Sensory perturbations in visual, auditory and tactile perception are core problems in fragile X syndrome (FXS). In the Fmr1 knockout mouse model of FXS, the maturation of synapses and circuits during critical period (CP) development in the somatosensory cortex is delayed, but it is unclear how this contributes to altered tactile sensory processing in the mature CNS. Here we demonstrate that inhibiting the juvenile chloride co-transporter NKCC1, which contributes to altered chloride homeostasis in developing cortical neurons of FXS mice, rectifies the chloride imbalance in layer IV somatosensory cortex neurons and corrects the development of thalamocortical excitatory synapses during the CP...
April 27, 2018: Molecular Psychiatry
https://www.readbyqxmd.com/read/29681800/early-retinal-defects-in-fmr1-y-mice-toward-a-critical-role-of-visual-dys-sensitivity-in-the-fragile-x-syndrome-phenotype
#8
Olivier Perche, Chloé Felgerolle, Maryvonne Ardourel, Audrey Bazinet, Arnaud Pâris, Rafaëlle Rossignol, Géraldine Meyer-Dilhet, Anne-Laure Mausset-Bonnefont, Betty Hébert, David Laurenceau, Céline Montécot-Dubourg, Arnaud Menuet, Jean-Charles Bizot, Jacques Pichon, Isabelle Ranchon-Cole, Sylvain Briault
Fragile X Syndrome (FXS) is caused by a deficiency in Fragile X Mental Retardation Protein (FMRP) leading to global sensorial abnormalities, among which visual defects represent a critical part. These visual defects are associated with cerebral neuron immaturity especially in the primary visual cortex. However, we recently demonstrated that retinas of adult Fmr1 -/y mice, the FXS murine model, present molecular, cellular and functional alterations. However, no data are currently available on the evolution pattern of such defects...
2018: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29645362/structural-plasticity-of-the-tdrd3-tudor-domain-probed-by-a-fragment-screening-hit
#9
Jiuyang Liu, Shuya Zhang, Mingqing Liu, Yaqian Liu, Gilbert Nshogoza, Jia Gao, Rongsheng Ma, Yang Yang, Jihui Wu, Jiahai Zhang, Fudong Li, Ke Ruan
As a reader of di-methylated arginine on various proteins, such as histone, RNA polymerase II, PIWI and Fragile X mental retardation protein, the Tudor domain of Tudor domain-containing protein 3 (TDRD3) mediates transcriptional activation in nucleus and formation of stress granules in the cytoplasm. Despite the TDRD3 implication in cancer cell proliferation and invasion, warheads to block the di-methylated arginine recognition pocket of the TDRD3 Tudor domain have not yet been uncovered. Here we identified 14 small molecule hits against the TDRD3 Tudor domain through NMR fragment-based screening...
April 12, 2018: FEBS Journal
https://www.readbyqxmd.com/read/29605426/translation-relevant-eeg-phenotypes-in-a-mouse-model-of-fragile-x-syndrome
#10
Jonathan W Lovelace, Iryna M Ethell, Devin K Binder, Khaleel A Razak
Identification of comparable biomarkers in humans and validated animal models will facilitate pre-clinical to clinical therapeutic pipelines to treat neurodevelopmental disorders. Fragile X Syndrome (FXS) is a leading known genetic cause of intellectual disability with symptoms that include increased anxiety, social and sensory processing deficits. Recent EEG studies in humans with FXS have identified neural oscillation deficits that include enhanced resting state gamma power and reduced inter-trial coherence of sound evoked gamma oscillations...
March 29, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29590342/protein-synthesis-levels-are-increased-in-a-subset-of-individuals-with-fragile-x-syndrome
#11
Sébastien Jacquemont, Laura Pacini, Aia E Jønch, Giulia Cencelli, Izabela Rozenberg, Yunsheng He, Laura D'Andrea, Giorgia Pedini, Marwa Eldeeb, Rob Willemsen, Fabrizio Gasparini, Flora Tassone, Randi Hagerman, Baltazar Gomez-Mancilla, Claudia Bagni
Fragile X syndrome (FXS) is a monogenic form of intellectual disability and autism spectrum disorder caused by the absence of the fragile X mental retardation protein (FMRP). In biological models for the disease, this leads to upregulated mRNA translation and as a consequence, deficits in synaptic architecture and plasticity. Preclinical studies revealed that pharmacological interventions restore those deficits, which are thought to mediate the FXS cognitive and behavioral symptoms. Here we characterized the de novo rate of protein synthesis in patients with FXS and their relationship with clinical severity...
March 24, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29486296/abnormal-hippocampal-theta-and-gamma-hypersynchrony-produces-network-and-spike-timing-disturbances-in-the-fmr1-ko-mouse-model-of-fragile-x-syndrome
#12
Tara Arbab, Francesco P Battaglia, Cyriel M A Pennartz, Conrado A Bosman
Neuronal networks can synchronize their activity through excitatory and inhibitory connections, which is conducive to synaptic plasticity. This synchronization is reflected in rhythmic fluctuations of the extracellular field. In the hippocampus, theta and gamma band LFP oscillations are a hallmark of the processing of spatial information and memory. Fragile X syndrome (FXS) is an intellectual disability and the most common genetic cause of autism spectrum disorder (Belmonte and Bourgeron, 2006). Here, we investigated how neuronal network synchronization in the mouse hippocampus is compromised by the Fmr1 mutation that causes FXS (Santos et al...
June 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29484980/innovative-therapeutic-potential-of-cannabinoid-receptors-as-targets-in-alzheimer-s-disease-and-less-well-known-diseases
#13
Juan A Paez, Nuria E Campillo
The discovery of cannabinoid receptors at the beginning of the 1990s, CB1 being cloned in 1990 and CB2 cloned in 1993, and the availability of selective and potent cannabimimetics could only be justified by the existence of endogenous ligands that are capable of binding to them. Thus, the characterisation and cloning of the first cannabinoid receptor (CB1) led to the isolation and characterisation of the first endocannabinoid, arachidonoylethanolamide (AEA), two years later and the subsequent identification of a family of lipid transmitters known as the fatty acid ester 2-arachidonoylglycerol (2-AG)...
February 25, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29481897/development-related-aberrations-in-kv1-1-%C3%AE-subunit-exert-disruptive-effects-on-bioelectrical-activities-of-neurons-in-a-mouse-model-of-fragile-x-syndrome
#14
Pingping Zhu, Jialing Li, Liting Zhang, Zhanrong Liang, Bin Tang, Wei-Ping Liao, Yong-Hong Yi, Tao Su
Kv1.1, a Shaker homologue potassium channel, plays a critical role in homeostatic regulation of neuronal excitability. Aberrations in the functional properties of Kv1.1 have been implicated in several neurological disorders featured by neuronal hyperexcitability. Fragile X syndrome (FXS), the most common form of inherited mental retardation, is characterized by hyperexcitability in neural network and intrinsic membrane properties. The Kv1.1 channel provides an intriguing mechanistic candidate for FXS. We investigated the development-related expression pattern of the Kv1...
June 8, 2018: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/29472612/sumoylation-regulates-fmrp-mediated-dendritic-spine-elimination-and-maturation
#15
Anouar Khayachi, Carole Gwizdek, Gwénola Poupon, Damien Alcor, Magda Chafai, Frédéric Cassé, Thomas Maurin, Marta Prieto, Alessandra Folci, Fabienne De Graeve, Sara Castagnola, Romain Gautier, Lenka Schorova, Céline Loriol, Marie Pronot, Florence Besse, Frédéric Brau, Emmanuel Deval, Barbara Bardoni, Stéphane Martin
Fragile X syndrome (FXS) is the most frequent inherited cause of intellectual disability and the best-studied monogenic cause of autism. FXS results from the functional absence of the fragile X mental retardation protein (FMRP) leading to abnormal pruning and consequently to synaptic communication defects. Here we show that FMRP is a substrate of the small ubiquitin-like modifier (SUMO) pathway in the brain and identify its active SUMO sites. We unravel the functional consequences of FMRP sumoylation in neurons by combining molecular replacement strategy, biochemical reconstitution assays with advanced live-cell imaging...
February 22, 2018: Nature Communications
https://www.readbyqxmd.com/read/29456084/rescue-of-fragile-x-syndrome-neurons-by-dna-methylation-editing-of-the-fmr1-gene
#16
X Shawn Liu, Hao Wu, Marine Krzisch, Xuebing Wu, John Graef, Julien Muffat, Denes Hnisz, Charles H Li, Bingbing Yuan, Chuanyun Xu, Yun Li, Dan Vershkov, Angela Cacace, Richard A Young, Rudolf Jaenisch
Fragile X syndrome (FXS), the most common genetic form of intellectual disability in males, is caused by silencing of the FMR1 gene associated with hypermethylation of the CGG expansion mutation in the 5' UTR of FMR1 in FXS patients. Here, we applied recently developed DNA methylation editing tools to reverse this hypermethylation event. Targeted demethylation of the CGG expansion by dCas9-Tet1/single guide RNA (sgRNA) switched the heterochromatin status of the upstream FMR1 promoter to an active chromatin state, restoring a persistent expression of FMR1 in FXS iPSCs...
February 22, 2018: Cell
https://www.readbyqxmd.com/read/29449635/purkinje-cells-derived-from-tsc-patients-display-hypoexcitability-and-synaptic-deficits-associated-with-reduced-fmrp-levels-and-reversed-by-rapamycin
#17
Maria Sundberg, Ivan Tochitsky, David E Buchholz, Kellen Winden, Ville Kujala, Kush Kapur, Deniz Cataltepe, Daria Turner, Min-Joon Han, Clifford J Woolf, Mary E Hatten, Mustafa Sahin
Accumulating evidence suggests that cerebellar dysfunction early in life is associated with autism spectrum disorder (ASD), but the molecular mechanisms underlying the cerebellar deficits at the cellular level are unclear. Tuberous sclerosis complex (TSC) is a neurocutaneous disorder that often presents with ASD. Here, we developed a cerebellar Purkinje cell (PC) model of TSC with patient-derived human induced pluripotent stem cells (hiPSCs) to characterize the molecular mechanisms underlying cerebellar abnormalities in ASD and TSC...
February 15, 2018: Molecular Psychiatry
https://www.readbyqxmd.com/read/29411265/rare-risk-variants-identification-by-identity-by-descent-mapping-and-whole-exome-sequencing-implicates-neuronal-development-pathways-in-schizophrenia-and-bipolar-disorder
#18
C Salvoro, S Bortoluzzi, A Coppe, G Valle, E Feltrin, M L Mostacciuolo, G Vazza
Schizophrenia (SCZ) and bipolar disorder (BPD) are highly heritable disorders with an estimated co-heritability of 68%. Hundreds of common alleles have been implicated, but recently a role for rare, high-penetrant variants has been also suggested in both disorders. This study investigated a familial cohort of SCZ and BPD patients from a closed population sample, where the high recurrence of the disorders and the homogenous genetic background indicate a possible enrichment in rare risk alleles. A total of 230 subjects (161 cases, 22 unaffected relatives, and 47 controls) were genetically investigated through an innovative strategy that integrates identity-by-descent (IBD) mapping and whole-exome sequencing (WES)...
February 6, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29398703/tandem-repeats-mediating-genetic-plasticity-in-health-and-disease
#19
REVIEW
Anthony J Hannan
Accumulating evidence suggests that many classes of DNA repeats exhibit attributes that distinguish them from other genetic variants, including the fact that they are more liable to mutation; this enables them to mediate genetic plasticity. The expansion of tandem repeats, particularly of short tandem repeats, can cause a range of disorders (including Huntington disease, various ataxias, motor neuron disease, frontotemporal dementia, fragile X syndrome and other neurological disorders), and emerging data suggest that tandem repeat polymorphisms (TRPs) can also regulate gene expression in healthy individuals...
May 2018: Nature Reviews. Genetics
https://www.readbyqxmd.com/read/29367010/chronic-minocycline-treatment-improves-hippocampal-neuronal-structure-nmda-receptor-function-and-memory-processing-in-fmr1-knockout-mice
#20
S Y Yau, Luis Bettio, M Vetrici, A Truesdell, C Chiu, J Chiu, E Truesdell, B R Christie
Fragile X Syndrome (FXS) is the most common inherited cause of intellectual disability, and is the leading known single-gene cause of autism spectrum disorder. FXS patients display varied behavioural deficits that include mild to severe cognitive impairments in addition to mood disorders. Currently there is no cure for this condition, however minocycline is becoming commonly prescribed as a treatment for FXS patients. Minocycline has been reported to alleviate social behavioural deficits, and improve verbal functioning in patients with FXS; however, its mode of action is not well understood...
May 2018: Neurobiology of Disease
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