A DNAzyme based knockdown model for Fragile-X syndrome in zebrafish reveals a critical window for therapeutic intervention

In this study, we have used a novel DNAzyme based approach to create a larval model of FXS in zebrafish with specific focus on the early developmental window.MethodsFmr1specific DNAzymes were electroporated into embryos to create theknockdown. Changes in RNA and protein levels of FMRP and relevant biomarkers were measured in the 0-7dpf window. Behavioral tests to measure anxiety, cognitive impairments and irritability in the larvae were conducted at the 7dpf stage. Drug treatment was carried out at various time points in the 0-7dpf window to identify the critical window for pharmacological intervention.ResultsThe DNAzyme based knockdown approach led to a significant knockdown of FMRP in the zebrafish embryos, accompanied by increased anxiety, irritability and cognitive impairments at 7dpf, thus creating a robust larval model of FXS. Treatment with the Mavoglurant was able to rescue the behavioral phenotypes in the FXS larvae, and found to be more efficacious in the 0-3dpf window.DiscussionThe results from this study have revealed that a) a DNAzyme based knockdown approach can be used to create robust larval zebrafish model of disease, in a high-throughput manner and b) optimal window for therapeutic intervention for FXS as well as other pediatric diseases with a monogenic cause can be identified using such a model.
Source: Journal of Pharmacological and Toxicological Methods - Category: Drugs & Pharmacology Source Type: research

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Abstract Fragile X syndrome (FXS) is a leading cause of heritable intellectual disability and autism. Humans with FXS show anxiety, sensory hypersensitivity and impaired learning. The mechanisms of learning impairments can be studied in the mouse model of FXS, the Fmr1 KO mouse, using tone-associated fear memory paradigms. Our previous study reported impaired development of parvalbumin (PV) positive interneurons and perineuronal nets (PNN) in the auditory cortex of Fmr1 KO mice. A recent study suggested PNN dynamics in the auditory cortex following tone-shock association is necessary for fear expression. Together ...
Source: Neurobiology of Learning and Memory - Category: Neurology Authors: Tags: Neurobiol Learn Mem Source Type: research
Albert Sanfeliu1, Karsten Hokamp2, Michael Gill1 and Daniela Tropea1,3*1Neuropsychiatric Genetics, Department of Psychiatry, School of Medicine, Trinity Translational Medicine Institute, St James Hospital, Dublin, Ireland2Department of Genetics, School of Genetics and Microbiology, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland3Department of Psychiatry, School of Medicine, Trinity College Institute for Neuroscience, Trinity College Dublin, Dublin, IrelandRett syndrome is a rare neuropsychiatric disorder with a wide symptomatology including impaired communication and movement, cardio-respiratory abno...
Source: Frontiers in Psychiatry - Category: Psychiatry Source Type: research
Publication date: Available online 5 December 2018Source: NeuroscienceAuthor(s): Teresa H. Wen, Jonathan W. Lovelace, Iryna M. Ethell, Devin K. Binder, Khaleel A. RazakAbstractFragile X Syndrome (FXS) is a leading genetic cause of autism and intellectual disabilities. Sensory processing deficits are common in humans with FXS and an animal model, the Fmr1 knockout (KO) mouse, manifesting in the auditory system as debilitating hypersensitivity and abnormal electroencephalographic (EEG) and event-related potential (ERP) phenotypes. FXS is a neurodevelopmental disorder, but how EEG/ERP phenotypes change during development is u...
Source: Neuroscience - Category: Neuroscience Source Type: research
Introduction: Fragile X Syndrome (FXS) is the leading form of inherited intellectual disability and autism spectrum disorder, caused by a tri-nucleotide CGG repeat expansion in the promoter region of the FMR1 gene [1]. The cognitive profile in FXS includes deficits in executive control and in visuospatial abilities, as well as in language and severe behavioural alterations with hyperactivity, impulsivity, anxiety: the condition often is associated with medical comorbidities among which epilepsy [1].
Source: Gait and Posture - Category: Orthopaedics Authors: Source Type: research
American Journal on Intellectual and Developmental Disabilities,Volume 122, Issue 5, Page 359-373, September 2017.
Source: American Journal on Intellectual and Developmental Disabilities - Category: Disability Authors: Source Type: research
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. Few investigations into the behavioral phenotype of the Fmr1 knockout mouse have also investigated females. The results of this study provide evidence for a sex‐specific...
Source: Brain and Behavior - Category: Neurology Authors: Tags: ORIGINAL RESEARCH Source Type: research
This study ’s other authors are Daniel Cantu, Anubhuti Goel, Shilpa Mantri and William Zeiger, all of UCLA.The study was funded by a Paul and Daisy Soros Fellowship for New Americans and an NIH NINDS F30 Fellowship (NS093719); UCLA Neural Microcircuits training grant (T32-NS058280); a Eugene V. Cota-Robles Fellowship; the UCLA Medical Scientist Training Program (NIH NIGMS training grant GM08042; and a Developmental Disabilities Translational Research Program grant (20160969) from the John Merck Fund; a SFARI grant from the Simons Foundation (295438); and NIH NICHD grant (RO1 HD054453).
Source: UCLA Newsroom: Health Sciences - Category: Universities & Medical Training Source Type: news
Abstract Fragile X syndrome (FXS) is an inheritable neuropsychological disease caused by expansion of the CGG trinucleotide repeat affecting the fmr1 gene on X chromosome, resulting in silence of the fmr1 gene and failed expression of FMRP. Patients with FXS suffer from cognitive impairment, sensory integration deficits, learning disability, anxiety, autistic traits, and so forth. Specifically, the morbidity of anxiety in FXS individuals remains high from childhood to adulthood. By and large, it is common that the change of brain plasticity plays a key role in the progression of disease. But for now, most studies ...
Source: Neural Plasticity - Category: Neurology Authors: Tags: Neural Plast Source Type: research
Researchers have new findings on fragile X, an autism-linked genetic disorder. Fragile X Syndrome (FXS) is an inherited cause of intellectual disability, especially among boys. It results in a spectrum of intellectual disabilities ranging from mild to severe, as well as physical characteristics, such as an elongated face, large or protruding ears, and large testes. Accompanying behavioral characteristics include stereotypic movements, such as hand-flapping, and social anxiety.
Source: ScienceDaily Headlines - Category: Science Source Type: news
ConclusionsThis study provides a preliminary description of repetitive behaviours in boys with FXS, which may form the groundwork for future research.
Source: Journal of Intellectual Disability Research - Category: Disability Authors: Tags: Original Manuscript Source Type: research
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