Limbic Epileptogenesis in a Mouse Model of Fragile X Syndrome

Qiu, Lifeng; Lu, Ting-Jia; Hu, Xiaoling; Yi, Yong‐Hong; Liao, Wei‐Ping; Xiong, Zhi‐Qi

doi:10.1093/cercor/bhn163

Cited by 29 publications

(21 citation statements)

References 62 publications

(70 reference statements)

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“…Only recently, a study on amygdala showed that Fmr1 KO mice have a more accelerated kindling development and longer electrographic seizure duration. Both NMDA antagonist, MK-801, and mGluR5 antagonist, MPEP, were able to repress accelerated rate of kindling development (Qiu et al 2009). …”

Section: Rescue Of the Fxs Behavioral Phenotypesmentioning

confidence: 99%

Molecular and Cellular Aspects of Mental Retardation in the Fragile X Syndrome: From Gene Mutation/s to Spine Dysmorphogenesis

Rubeis

Fernández

Buzzi

et al. 2012

Synaptic Plasticity

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The Fragile X syndrome (FXS) is the most frequent form of inherited mental retardation and also considered a monogenic cause of Autism Spectrum Disorder. FXS symptoms include neurodevelopmental delay, anxiety, hyperactivity, and autistic-like behavior. The disease is due to mutations or loss of the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein abundant in the brain and gonads, the two organs mainly affected in FXS patients. FMRP has multiple functions in RNA metabolism, including mRNA decay, dendritic targeting of mRNAs, and protein synthesis. In neurons lacking FMRP, a wide array of mRNAs encoding proteins involved in synaptic structure and function are altered. As a result of this complex dysregulation, in the absence of FMRP, spine morphology and functioning is impaired. Consistently, model organisms for the study of the syndrome recapitulate the phenotype observed in FXS patients, such as dendritic spine anomalies and defects in learning. Here, we review the fundamentals of genetic and clinical aspects of FXS, devoting a specific attention to ASD comorbidity and FXS-related diseases. We also review the current knowledge on FMRP functions through structural, molecular, and cellular findings. Finally, we discuss the neuroanatomical, electrophysiological, and behavioral defects caused by FMRP loss, as well as the current treatments able to partially revert some of the FXS abnormalities.

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Section: Rescue Of the Fxs Behavioral Phenotypesmentioning

confidence: 99%

Molecular and Cellular Aspects of Mental Retardation in the Fragile X Syndrome: From Gene Mutation/s to Spine Dysmorphogenesis

Rubeis

Fernández

Buzzi

et al. 2012

Synaptic Plasticity

View full text Add to dashboard Cite

show abstract

“…Higher susceptibility to audiogenic seizures is reliably observed in Fmr1 KO mice of various genetic backgrounds and has become very useful to evaluate potential therapeutic strategies (Musumeci et al, 2000;Yan et al, 2004Yan et al, , 2005Dolen et al, 2007;Min et al, 2009). Recently, a kindling paradigm similarly revealed differences in seizure susceptibility in wild-type and Fmr1 KO mice (Qiu et al, 2009). If reproducible, this seizure paradigm might become an additional tool to assess hyperexcitability in the future.…”

Section: The Behavioral Phenotype Of Fmr1 Mouse Modelsmentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Groß

Berry‐Kravis

Bassell

2011

Neuropsychopharmacol

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Fragile X syndrome (FXS) is an inherited neurodevelopmental disease caused by loss of function of the fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group 1 metabotropic glutamate receptors is elevated and insensitive to stimulation, which may underlie many of the neurological and neuropsychiatric features of FXS. Treatment of FXS animal models with negative allosteric modulators of these receptors and preliminary clinical trials in human patients support the hypothesis that metabotropic glutamate receptor signaling is a valuable therapeutic target in FXS. However, recent research has also shown that FMRP may regulate diverse aspects of neuronal signaling downstream of several cell surface receptors, suggesting a possible new route to more direct disease-targeted therapies. Here, we summarize promising recent advances in basic research identifying and testing novel therapeutic strategies in FXS models, and evaluate their potential therapeutic benefits. We provide an overview of recent and ongoing clinical trials motivated by some of these findings, and discuss the challenges for both basic science and clinical applications in the continued development of effective disease mechanism-targeted therapies for FXS.

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“…Without this feedback, Fmr1 −/− mice have enhanced mGluR5-dependent hippocampal 100,101 and cerebellar LTD 82. Over-activation of mGluR5 receptors also increases seizure susceptibility 102,103. Together these results support the mGluR theory of FXS and provide a framework for the development of new therapies 98 (Fig.…”

Section: Neurodevelopmental Disordersmentioning

confidence: 59%

Emerging Pharmacotherapies for Neurodevelopmental Disorders

Wetmore

Garner

2010

Journal of Developmental &Amp; Behavioral Pediatrics

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A growing and interdisciplinary translational neuroscience research effort for neurodevelopmental disorders (NDDs) is investigating the mechanisms of dysfunction and testing effective treatment strategies in animal models and, when possible, in the clinic. NDDs with a genetic basis have received particular attention. Transgenic animals that mimic genetic insults responsible for disease in man have provided insight about mechanisms of dysfunction, and, surprisingly, have shown that cognitive deficits can be addressed in adult animals. This review will present recent translational research based on animal models of genetic NDDs, as well as pharmacotherapeutic strategies under development to address deficits of brain function for Down syndrome, fragile X syndrome, Rett syndrome, neurofibromatosis-1, tuberous sclerosis, and autism. Although these disorders vary in underlying causes and clinical presentation, common pathways and mechanisms for dysfunction have been observed. These include abnormal gene dosage, imbalance among neurotransmitter systems, and deficits in the development, maintenance and plasticity of neuronal circuits. NDDs affect multiple brain systems and behaviors that may be amenable to drug therapies that target distinct deficits. A primary goal of translational research is to replace symptomatic and supportive drug therapies with pharmacotherapies based on a principled understanding of the causes of dysfunction. Based on this principle, several recently developed therapeutic strategies offer clear promise for clinical development in man.

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Limbic Epileptogenesis in a Mouse Model of Fragile X Syndrome

Cited by 29 publications

References 62 publications

Molecular and Cellular Aspects of Mental Retardation in the Fragile X Syndrome: From Gene Mutation/s to Spine Dysmorphogenesis

Molecular and Cellular Aspects of Mental Retardation in the Fragile X Syndrome: From Gene Mutation/s to Spine Dysmorphogenesis

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Emerging Pharmacotherapies for Neurodevelopmental Disorders

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