Fragile X: Translation in Action

Bear, Mark F.; Dölen, Gül; Osterweil, Emily K.; Nagarajan, Naveen

doi:10.1038/sj.npp.1301610

Cited by 92 publications

(73 citation statements)

References 25 publications

(25 reference statements)

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“…Neuropathological studies of human brain as well as studies in a mouse model of fragile-X syndrome showed that neuronal architecture is abnormal in fragile X syndrome with long, thin and tortuous dendritic spines which appear immature (33). Fragile X syndrome is caused by a loss of function mutation in the fragile-X mental retardation protein (FMRP), an mRNA binding protein that regulates translation (34). In 2002 Huber et al reported that LTD is increased in the hippocampus from mice without FMRP (35).…”

Section: Neuronal Plasticity In Fragile X Syndromementioning

confidence: 99%

Plasticity and injury in the developing brain

Johnston¹,

Ishida²,

Ishida³

et al. 2009

Brain and Development

197

125

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The child's brain is more malleable or plastic than that of adults and this accounts for the ability of children to learn new skills quickly or recovery from brain injuries. Several mechanisms contribute to this ability including overproduction and deletion of neurons and synapses, and activity-dependent stabilization of synapses. The molecular mechanisms for activity dependent synaptic plasticity are being discovered and this is leading to a better understanding of the pathogenesis of several disorders including neurofibromatosis, tuberous sclerosis, Fragile X syndrome and Rett syndrome. Many of the same pathways involved in synaptic plasticity, such as glutamate-mediated excitation, can also mediate brain injury when the brain is exposed to stress or energy failure such as hypoxia-ischemia. Recent evidence indicates that cell death pathways activated by injury differ between males and females. This new information about the molecular pathways involved in brain plasticity and injury are leading to insights that will provide better therapies for pediatric neurological disorders. KeywordsPlasticity; Injury; Fragile X Syndrome; Rett Syndrome; Hypoxia-Ischemia; NMDA; AMPA; Periventricular Leukomalacia Many disorders and injuries of the developing brain affect the basic mechanisms that allow the nervous system to be shaped by experience during childhood. These mechanisms provide the substrate for brain plasticity (kasosei in Japanese), which is much more active in children than in adults. Plasticity in the child's brain is enhanced because the organization of networks of *Correspondence: 707 North Broadway, Baltimore, MD 21205, Fax: 443-923-9317 Phone: 443-923-9315, Johnston@kennedykrieger.org. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. neuronal synapses as well as white matter pathways remain "under construction" well into adolescence and even later(1). Accordingly, the effects of intensive learning in school, exposure to a second language or practice in athletics has a much greater impact on children than adults. Several neurobiological mechanism contribute to brain plasticity, including an over-production of neurons in early development, apoptosis or programmed cell death of excessive neurons, overproduction and elimination of immature synapses in childhood, and continuous stabilization and strengthening of synaptic connections later in life(2). In this review we focus on some mechanisms for synaptic plasticity, and emerging evidence that these processes are disrupted in several pediatric neurological disorders. NIH Public Access Synaptic PlasticitySynaptic p...

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Section: Neuronal Plasticity In Fragile X Syndromementioning

confidence: 99%

Plasticity and injury in the developing brain

Johnston¹,

Ishida²,

Ishida³

et al. 2009

Brain and Development

197

125

View full text Add to dashboard Cite

show abstract

“…A prominent phenotype of the FXS mouse model is increased and stimulusinsensitive protein synthesis, which leads to impairments of several protein synthesis-dependent forms of synaptic plasticity (5,6). To test whether dysregulated protein synthesis in the absence of FMRP can be detected in nonneuronal, peripheral cells from human patients with FXS, we quantified protein synthesis rates in lymphoblastoid cell lines (LCLs) from a healthy control (called "Ctr" in figures and legends) and a patient with FXS that carried the full mutation, that is, completely methylated trinucleotide expansion in the FMR1 gene (subsequently called FXS cells).…”

Section: Dysregulated Protein Synthesis In Fxs Patient Lymphoblastoidmentioning

confidence: 99%

“…A standard curve was used to quantify the amount of phosphatidylinositol (3,4,5) triphosphate present after the reaction.…”

Section: Elisa Pi3k Assaysmentioning

confidence: 99%

“…The analysis of animal models has shown that absence of FMRP causes pathological changes in the regulation of basal and stimulus-induced protein synthesis in the brain (1)(2)(3)(4). These changes in neuronal protein expression are believed to underlie or contribute to most of the neuronal dysfunctions observed in FXS (5). FMRP is an mRNA binding protein shown to regulate translation, localization and stability of many target mRNAs (6).…”

Section: Introductionmentioning

confidence: 99%

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Excess Protein Synthesis in FXS Patient Lymphoblastoid Cells Can Be Rescued with a p110β-Selective Inhibitor

Groß

Bassell

2011

Mol Med

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“…In the Fmr1 knockout, negative regulation is lost leading to enhanced mGlu5 receptor signaling . These studies led to the prediction that mGlu5 receptor antagonists should restore the normal synaptic balance and thus improve behavioral phenotypes (Bear et al, 2008).…”

Section: Intracellular Mglu5mentioning

confidence: 99%

Location-Dependent Signaling of the Group 1 Metabotropic Glutamate Receptor mGlu5

et al. 2014

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Although G protein-coupled receptors are primarily known for converting extracellular signals into intracellular responses, some receptors, such as the group 1 metabotropic glutamate receptor, mGlu5, are also localized on intracellular membranes where they can mediate both overlapping and unique signaling effects. Thus, besides "ligand bias," whereby a receptor's signaling modality can shift from G protein dependence to independence, canonical mGlu5 receptor signaling can also be influenced by "location bias" (i.e., the particular membrane and/or cell type from which it signals). Because mGlu5 receptors play important roles in both normal development and in disorders such as Fragile X syndrome, autism, epilepsy, addiction, anxiety, schizophrenia, pain, dyskinesias, and melanoma, a large number of drugs are being developed to allosterically target this receptor. Therefore, it is critical to understand how such drugs might be affecting mGlu5 receptor function on different membranes and in different brain regions. Further elucidation of the site(s) of action of these drugs may determine which signal pathways mediate therapeutic efficacy.

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Fragile X: Translation in Action

Cited by 92 publications

References 25 publications

Plasticity and injury in the developing brain

Plasticity and injury in the developing brain

Excess Protein Synthesis in FXS Patient Lymphoblastoid Cells Can Be Rescued with a p110β-Selective Inhibitor

Location-Dependent Signaling of the Group 1 Metabotropic Glutamate Receptor mGlu5

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