Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0025362 (mental retardation)
15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein synthesis occurs in neuronal dendrites, often near synapses. Polyribosomal aggregates often appear in dendritic spines, particularly during development. Polyribosomal aggregates in spines increase during experience-dependent synaptogenesis, e.g., in rats in a complex environment. Some protein synthesis appears to be regulated directly by synaptic activity. We use "synaptoneurosomes," a preparation highly enriched in pinched-off, resealed presynaptic processes attached to resealed postsynaptic processes that retain normal functions of neurotransmitter release, receptor activation, and various postsynaptic responses including signaling pathways and protein synthesis. We have found that, when synaptoneurosomes are stimulated with glutamate or group I metabotropic glutamate receptor agonists such as dihydroxyphenylglycine, mRNA is rapidly taken up into polyribosomal aggregates, and labeled methionine is incorporated into protein. One of the proteins synthesized is FMRP, the protein that is reduced or absent in fragile X mental retardation syndrome. FMRP has three RNA-binding domains and reportedly binds to a significant number of mRNAs. We have found that dihydroxyphenylglycine-activated protein synthesis in synaptoneurosomes is dramatically reduced in a knockout mouse model of fragile X syndrome, which cannot produce full-length FMRP, suggesting that FMRP is involved in or required for this process. Studies of autopsy samples from patients with fragile X syndrome have indicated that dendritic spines may fail to assume a normal mature size and shape and that there are more spines per unit dendrite length in the patient samples. Similar findings on spine size and shape have come from studies of the knockout mouse. Study of the development of the somatosensory cortical region containing the barrel-like cell arrangements that process whisker information suggests that normal dendritic regression is impaired in the knockout mouse. This finding suggests that FMRP may be required for the normal processes of maturation and elimination to occur in cerebral cortical development.
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PMID:Synaptic regulation of protein synthesis and the fragile X protein. 1141 94

Fragile X syndrome is the most common cause of mental retardation known to be inherited. The syndrome results from the suppressed expression of a single protein, the fragile X mental retardation protein (FMRP). Understanding the function and regulation of FMRP can, therefore, offer insights into both the pathophysiology of fragile X syndrome and the molecular mechanisms of learning and memory. We provide an overview of current concepts of how FMRP functions in the nervous system, with special emphasis on recent evidence that FMRP has a role in metabotropic glutamate receptor-activated protein translation and synaptic plasticity.
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PMID:Fragile X mental retardation protein in plasticity and disease. 1242 29

Fragile X syndrome is a common inherited cause of mental retardation that results from the absence of the Fragile X Mental Retardation Protein (FMRP), an RNA binding protein thought to regulate translation of bound mRNAs, including its own. Previous studies in our laboratory have shown that FMRP expression increases in the barrel cortex of the rat after unilateral whisker stimulation, a model of experience dependent plasticity. This increase in protein is restricted to sub-cellular fractions enriched for synaptic or poly-ribosomal complexes. Here, we demonstrate that these increases are not accompanied by a change in FMR-1 mRNA levels and that they are blocked by the protein synthesis inhibitor cycloheximide in a dose dependent manner. Whisker stimulation dependent expression of FMRP is also abolished by pharmacological blockade of either NMDA receptors (MK-801, 0.25 mg/kg) or type I metabotropic glutamate receptors (AIDA, 5 mg/kg). In primary cortical neurons, activation of type I mGluRs leads to an increase in FMRP expression that is not effected by blockade of NMDA receptors. Taken together, these studies show that experience regulates FMRP production in vivo at the level of translation and supports a role for FMRP in metabotropic glutamate receptor mediated synaptic plasticity.
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PMID:Whisker stimulation-dependent translation of FMRP in the barrel cortex requires activation of type I metabotropic glutamate receptors. 1259 Nov 63

Fragile X syndrome (FXS) is a common inherited cause of mental retardation resulting from the absence of the fragile X mental retardation protein (FMRP). FMRP is thought to regulate the translation of target mRNAs, including its own transcript. Here we show that the levels of FMRP are rapidly up-regulated in primary cortical neurons in response to the type-I metabotropic glutamate receptor (mGluR) agonist S-3,5-dihydrophenylglycine. These changes require new protein synthesis but not transcription and are specific to mGluR activation. We also demonstrate that the mRNA for PSD-95, a scaffolding protein involved in synaptic plasticity, contains a highly conserved canonical binding site for FMRP within its 3' UTR. Furthermore, PSD-95 is rapidly translated in response to S-3,5-dihydrophenylglycine. Finally, we show that these mGluR-dependent changes in PSD-95 expression are lost in neurons derived from FMRP knockout mice, a model of FXS. Taken together, these studies suggest that FMRP is required for mGluR-dependent translation of PSD-95 and provide insights into the pathophysiology of FXS.
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PMID:The fragile X mental retardation protein is required for type-I metabotropic glutamate receptor-dependent translation of PSD-95. 1461 33

Fragile X syndrome is a leading heritable cause of mental retardation that results from the loss of FMR1 gene function. A Drosophila model for Fragile X syndrome, based on the loss of dfmr1 activity, exhibits phenotypes that bear similarity to Fragile X-related symptoms. Herein, we demonstrate that treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium can rescue courtship and mushroom body defects observed in these flies. Furthermore, we demonstrate that dfmr1 mutants display cognitive deficits in experience-dependent modification of courtship behavior, and treatment with mGluR antagonists or lithium restores these memory defects. These findings implicate enhanced mGluR signaling as the underlying cause of the cognitive, as well as some of the behavioral and neuronal, phenotypes observed in the Drosophila Fragile X model. They also raise the possibility that compounds having similar effects on metabotropic glutamate receptors may ameliorate cognitive and behavioral defects observed in Fragile X patients.
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PMID:Pharmacological rescue of synaptic plasticity, courtship behavior, and mushroom body defects in a Drosophila model of fragile X syndrome. 1574 38

Fragile X Syndrome is the most common form of inherited mental retardation worldwide. A Fragile X mouse model, fmr1(tm1Cgr), with a disruption in the X-linked Fmr1 gene, has three substantial deficits observed in several strains: (1) sensitivity to audiogenic seizures (AGS), (2) tendency to spend significantly more time in the center of an open field, and (3) enlarged testes. Alterations in metabotropic glutamate receptor group I signaling were previously identified in the fmr1(tm1Cgr) mouse. In this study, we examined the effect of MPEP, an antagonist of the group I metabotropic glutamate receptor mGluR5, on audiogenic seizures and open field activity of fmr1(tm1Cgr) mice. Genetic analysis revealed synergistic reactions between fmr1(tm1Cgr) and inbred AGS alleles. In addition, AGS sensitivity due to the fmr1(tm1Cgr) allele was restricted during development. Examination of phenotypes combining mGluR5 inhibition and Fmr1 mutation indicated that absence of FMRP may affect mGluR5 signaling through indirect as well as direct pathways. All strains of fmr1(tm1Cgr) mice tested (FVB/NJ, C57BL/6J, and an F1 hybrid of the two) had a more excitable AGS pathway than wild-type, and consequently required more MPEP to achieve seizure suppression. At high doses of mGluR5 antagonists, a Fragile X specific tolerance (loss of drug activity) was observed. The tolerance effect could be overcome by a further increase in drug dose. In open field tests, MPEP reduced fmr1(tm1Cgr) center field behavior to one indistinguishable from wild-type. Therefore, mGluR5 antagonists were able to rescue two of the major phenotypes of the FX mouse. Modulation of mGluR5 signaling may allow amelioration of symptoms of Fragile X Syndrome.
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PMID:Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. 1605 74

Mutations in FMR1, which encodes the fragile X mental retardation protein (FMRP), are the cause of fragile X syndrome (FXS), an X-linked mental retardation disorder. Inactivation of the mouse gene Fmr1 confers a number of FXS-like phenotypes including an enhanced susceptibility to epileptogenesis during development. We find that in a FXS mouse model, in which the function of FMRP is suppressed, synaptically released glutamate induced prolonged epileptiform discharges resulting from enhanced group I metabotropic glutamate receptor (mGluR)-mediated responses in hippocampal slices. The induction of the group I mGluR-mediated, prolonged epileptiform discharges was inhibited in preparations that were pretreated with inhibitors of ERK1/2 (extracellular signal-regulated kinase 1/2) phosphorylation or of mRNA translation, and their maintenance was suppressed by group I mGluR antagonists. The results suggest that FMRP plays a key role in the control of signaling at the recurrent glutamatergic synapses in the hippocampus. The absence of this control causes the synaptically activated group I mGluRs to elicit translation-dependent epileptogenic activities.
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PMID:Prolonged epileptiform discharges induced by altered group I metabotropic glutamate receptor-mediated synaptic responses in hippocampal slices of a fragile X mouse model. 1613 62

Genetic abnormalities frequently give rise to a mental retardation phenotype. Recent advances in resolution of comparative genomic hybridization and genomic sequence annotation has identified new syndromes at chromosome 3q29 and 9q34. The finding of a significant number of copy number polymorphisms in the genome in the normal population, means that assigning pathogenicity to deletions and duplications in patients with mental retardation can be difficult but has been identified for duplications of MECP2 and L1CAM. Novel autosomal genes that cause mental retardation have been identified recently including CC2D1A identified by homozygosity mapping. Several new genes and pathways have been identified in the field of X-linked mental retardation but many more still await identification. Analysis of families where only a single male is affected reveals that the chance of this being due to a single X-linked gene abnormality is significantly less than would be expected if the excess of males in the population is entirely due to X-linked disease. Recent identification of novel X-linked mental retardation genes has identified components of the post-synaptic density and multiple zinc finger transcription factors as disease causing suggesting new mechanisms of disease causation. The first therapeutic treatments of animal models of mental retardation have been reported, a Drosophila model of Fragile X syndrome has been treated with lithium or metabotropic glutamate receptor (mGluR) antagonists and a mouse model of NF1 has been treated with the HMG-CoA reductase inhibitor lavastatin, which improves the learning and memory skills in these models.
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PMID:The genetics of mental retardation. 1698 73

Fragile X syndrome is a common heritable form of mental retardation in humans. Recent neuroanatomical studies indicate an apparent immature appearance of neurons in fragile X syndrome patients and fragile X mental retardation protein (FMRP)-knockout mice, an animal model of this condition. In this work, we investigated possible alterations in synaptic plasticity in the neocortex of FMRP-knockout mice. Extracellular field potentials were recorded from the deep-layer visual neocortex. Long-term potentiation (LTP) was severely attenuated in brain slices from knockout mice relative to that observed in slices from wild-type mice. Considering that neocortical LTP can involve both NMDA receptor-dependent and -independent mechanisms, we attempted to distinguish the nature of LTP attenuated in the knockout condition. In slices from wild-type mice, LTP was partially attenuated by the NMDA receptor antagonist 3-[(+/-)-2-carboxypiperazin-4-yl]-propyl-1-phosphate (CPP); however, the general metabotropic glutamate receptor (mGluR) antagonist alpha-methyl-4-carboxyphenylglycine (MCPG) strongly attenuated LTP, resulting in a response indistinguishable from that observed in slices from knockout mice. The selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) attenuated LTP to a similar degree as did MCPG in wild-type slices, but MPEP did not alter the reduced potentiation in knockout slices. Our results suggest that LTP in layer V visual neocortex depends primarily on mGluR5 activation. Our data also indicate that mGluR5-mediated synaptic plasticity is absent in the neocortex of FMRP-knockout mice. Such an alteration may contribute to the cognitive and learning deficits exhibited in these mice as well as in fragile X syndrome.
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PMID:Absence of metabotropic glutamate receptor-mediated plasticity in the neocortex of fragile X mice. 1728 48

Amyloid precursor protein (APP) facilitates synapse formation in the developing brain, while beta-amyloid (Abeta) accumulation, which is associated with Alzheimer disease, results in synaptic loss and impaired neurotransmission. Fragile X mental retardation protein (FMRP) is a cytoplasmic mRNA binding protein whose expression is lost in fragile X syndrome. Here we show that FMRP binds to the coding region of APP mRNA at a guanine-rich, G-quartet-like sequence. Stimulation of cortical synaptoneurosomes or primary neuronal cells with the metabotropic glutamate receptor agonist DHPG increased APP translation in wild-type but not fmr-1 knockout samples. APP mRNA coimmunoprecipitated with FMRP in resting synaptoneurosomes, but the interaction was lost shortly after DHPG treatment. Soluble Abeta40 or Abeta42 levels were significantly higher in multiple strains of fmr-1 knockout mice compared to wild-type controls. Our data indicate that postsynaptic FMRP binds to and regulates the translation of APP mRNA through metabotropic glutamate receptor activation and suggests a possible link between Alzheimer disease and fragile X syndrome.
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PMID:FMRP mediates mGluR5-dependent translation of amyloid precursor protein. 2007 62


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