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)

Growing evidence indicates that both seizure (glutamate) and cocaine (dopamine) treatment modulate synaptic plasticity within the mesolimbic region of the CNS. Activation of glutamatergic neurons depends on the localized translation of neuronal mRNA products involved in modulating synaptic plasticity. In this study, we demonstrate the dendritic localization of HuR and HuD RNA-binding proteins (RBPs) and their association with neuronal mRNAs following these two paradigms of seizure and cocaine treatment. Both the ubiquitously expressed HuR and neuronal HuD RBPs were detected in different regions as well as within dendrites of the brain and in dissociated neurons. Quantitative analysis revealed an increase in HuR, HuD and p-glycogen synthase kinase 3beta (GSK3beta) protein levels as well as neuronal mRNAs encoding Homer, CaMKIIalpha, vascular early response gene, GAP-43, neuritin, and neuroligin protein products following either seizure or cocaine treatment. Inhibition of the Akt/GSK3beta signaling pathway by acute or chronic LiCl treatment revealed changes in HuR, HuD, pGSK3beta, p-Akt, and beta-catenin protein levels. In addition, a genetically engineered hyperdopaminergic mouse model (dopamine transporter knockout) revealed decreased expression of HuR protein levels, but no significant change was observed in HuD or fragile-X mental retardation protein RBPs. Finally, our data suggest that HuR and HuD RBPs potentially interact directly with neuronal mRNAs important for differentiation and synaptic plasticity.
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PMID:Activity-dependent expression of ELAV/Hu RBPs and neuronal mRNAs in seizure and cocaine brain. 1901 79

Loss of the mRNA-binding protein FMRP results in the most common inherited form of both mental retardation and autism spectrum disorders: fragile X syndrome (FXS). The leading FXS hypothesis proposes that metabotropic glutamate receptor (mGluR) signaling at the synapse controls FMRP function in the regulation of local protein translation to modulate synaptic transmission strength. In this study, we use the Drosophila FXS disease model to test the relationship between Drosophila FMRP (dFMRP) and the sole Drosophila mGluR (dmGluRA) in regulation of synaptic function, using two-electrode voltage-clamp recording at the glutamatergic neuromuscular junction (NMJ). Null dmGluRA mutants show minimal changes in basal synapse properties but pronounced defects during sustained high-frequency stimulation (HFS). The double null dfmr1;dmGluRA mutant shows repression of enhanced augmentation and delayed onset of premature long-term facilitation (LTF) and strongly reduces grossly elevated post-tetanic potentiation (PTP) phenotypes present in dmGluRA-null animals. Null dfmr1 mutants show features of synaptic hyperexcitability, including multiple transmission events in response to a single stimulus and cyclic modulation of transmission amplitude during prolonged HFS. The double null dfmr1;dmGluRA mutant shows amelioration of these defects but does not fully restore wildtype properties in dfmr1-null animals. These data suggest that dmGluRA functions in a negative feedback loop in which excess glutamate released during high-frequency transmission binds the glutamate receptor to dampen synaptic excitability, and dFMRP functions to suppress the translation of proteins regulating this synaptic excitability. Removal of the translational regulator partially compensates for loss of the receptor and, similarly, loss of the receptor weakly compensates for loss of the translational regulator.
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PMID:Metabotropic glutamate receptor-mediated use-dependent down-regulation of synaptic excitability involves the fragile X mental retardation protein. 1903 65

Fragile X syndrome is one of the most common forms of mental retardation, yet little is known about the physiological mechanisms causing the disease. In this study, we probed the ionotropic glutamate receptor content in synapses of hippocampal CA1 pyramidal neurons in a mouse model for fragile X (Fmr1 KO2). We found that Fmr1 KO2 mice display a significantly lower AMPA to NMDA ratio than wild-type mice at 2 weeks of postnatal development but not at 6-7 weeks of age. This ratio difference at 2 weeks postnatally is caused by down-regulation of the AMPA and up-regulation of the NMDA receptor components. In correlation with these changes, the induction of NMDA receptor-dependent long-term potentiation following a low-frequency pairing protocol is increased in Fmr1 KO2 mice at this developmental stage but not later in maturation. We propose that ionotropic glutamate receptors, as well as potentiation, are altered at a critical time point for hippocampal network development, causing long-term changes. Associated learning and memory deficits would contribute to the fragile X mental retardation phenotype.
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PMID:Synaptic ionotropic glutamate receptors and plasticity are developmentally altered in the CA1 field of Fmr1 knockout mice. 1921 22

Cerebral palsy due to perinatal injury to cerebral white matter is usually not caused by genetic mutations, but by ischemia and/or inflammation. Here, we describe an autosomal-recessive type of tetraplegic cerebral palsy with mental retardation, reduction of cerebral white matter, and atrophy of the cerebellum in an inbred sibship. The phenotype was recorded and evolution followed for over 20 years. Brain lesions were studied by diffusion tensor MR tractography. Homozygosity mapping with SNPs was performed for identification of the chromosomal locus for the disease. In the 14 Mb candidate region on chromosome 7q22, RNA expression profiling was used for selecting among the 203 genes in the area. In postmortem brain tissue available from one patient, histology and immunohistochemistry were performed. Disease course and imaging were mostly reminiscent of hypoxic-ischemic tetraplegic cerebral palsy, with neuroaxonal degeneration and white matter loss. In all five patients, a donor splice site pathogenic mutation in intron 14 of the AP4M1 gene (c.1137+1G-->T), was identified. AP4M1, encoding for the mu subunit of the adaptor protein complex-4, is involved in intracellular trafficking of glutamate receptors. Aberrant GluRdelta2 glutamate receptor localization and dendritic spine morphology were observed in the postmortem brain specimen. This disease entity, which we refer to as congenital spastic tetraplegia (CST), is therefore a genetic model for congenital cerebral palsy with evidence for neuroaxonal damage and glutamate receptor abnormality, mimicking perinatally acquired hypoxic-ischemic white matter injury.
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PMID:Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy. 1955 97

Functional absence of fragile X mental retardation protein (FMRP) causes the fragile X syndrome, a hereditary form of mental retardation characterized by a change in dendritic spine morphology. The RNA-binding protein FMRP has been implicated in regulating postsynaptic protein synthesis. Here we have analyzed whether the abundance of scaffold proteins and neurotransmitter receptor subunits in postsynaptic densities (PSDs) is altered in the neocortex and hippocampus of FMRP-deficient mice. Whereas the levels of several PSD components are unchanged, concentrations of Shank1 and SAPAP scaffold proteins and various glutamate receptor subunits are altered in both adult and juvenile knock-out mice. With the exception of slightly increased hippocampal SAPAP2 mRNA levels in adult animals, altered postsynaptic protein concentrations do not correlate with similar changes in total and synaptic levels of corresponding mRNAs. Thus, loss of FMRP in neurons appears to mainly affect the translation and not the abundance of particular brain transcripts. Semi-quantitative analysis of RNA levels in FMRP immunoprecipitates showed that in the mouse brain mRNAs encoding PSD components, such as Shank1, SAPAP1-3, PSD-95, and the glutamate receptor subunits NR1 and NR2B, are associated with FMRP. Luciferase reporter assays performed in primary cortical neurons from knock-out and wild-type mice indicate that FMRP silences translation of Shank1 mRNAs via their 3'-untranslated region. Activation of metabotropic glutamate receptors relieves translational suppression. As Shank1 controls dendritic spine morphology, our data suggest that dysregulation of Shank1 synthesis may significantly contribute to the abnormal spine development and function observed in brains of fragile X syndrome patients.
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PMID:Fragile X mental retardation protein regulates the levels of scaffold proteins and glutamate receptors in postsynaptic densities. 1964 Aug 47

It has been suggested that overexpression of neuronal Ca2+ sensor-1 (NCS-1) protein is implicated in the pathophysiology of neurodisorders such as schizophrenia, bipolar disturbance and X-linked mental retardation. The mechanism by which NCS-1 would be involved in the causes and/or consequences of these neurodisorders is still far from elucidation. Independent evidence has pointed NCS-1 as a key regulator of synaptic efficacy by altering the expression and activity of voltage-gated channels, inhibiting internalization of dopaminergic receptors, and altering phosphoinositide metabolism. In this study, we examined the possible participation of NCS-1 protein in signal transmission dependent on muscarinic receptor activation, using PC12 cells stably expressing NCS-1 (PC12-NCS-1). Carbachol (CCH; 300 microM) was able to evoke glutamate release more efficiently from PC12-NCS-1 (15.3+/-1.0nmol/mg of protein) than wild type cells (PC12-wt; 8.3+/-0.9nmol/mg of protein). This increase of glutamate release induced by CCH was independent on extracellular Ca2+ influx. Additionally, a larger increase of cytoplasmic levels of InsP3 (663.0+/-63.0 and 310.0+/-39.0% of fluorescence in A.U.) and [Ca2+]i (766.4+/-40.0 and 687.8+/-37.1nmol/L) was observed after CCH stimulus of PC12-NCS-1 compared with PC12-wt. Clearly distinction between intracellular Ca2+ dynamics was also observed in PC12-NCS-1 and PC12-wt. A larger increase followed by fast decay of [Ca2+]i was observed in PC12-NCS-1. A plateau with a delayed decay of [Ca2+]i was characteristic of PC12-wt [Ca2+]i response. Both enhancement of InsP3 production and glutamate release observed in PC12-NCS-1 were blocked by atropine (10 microM). Together, our data show that overexpression of NCS-1 in PC12 cells induces an enhancement of intracellular second messenger and transmitter release dependent on CCH response, suggesting that muscarinic signaling is "up-regulated" in this cell model.
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PMID:Modulation of muscarinic signaling in PC12 cells overexpressing neuronal Ca2+ sensor-1 protein. 1965 67

Fragile X syndrome, the main cause of inherited mental retardation, is caused by transcriptional silencing of the fragile X mental retardation gene, FMR1. Absence of the associated protein FMRP leads to the dysregulation of many genes creating a phenotype of ADHD, anxiety, epilepsy and autism. The core aim of this review is to summarise two decades of molecular research leading to the characterisation of cellular and molecular pathways involved in the pathology of this disease and as a consequence to the identification of two new promising targets for rational therapy of fragile X syndrome, namely the group 1 metabotrope glutamate receptors (Gp1 mGluRs) and the gamma-amino butyric acid A receptors (GABA(A)Rs). As no current clinical treatments are directed specifically at the underlying neuronal defect due to absence of FMRP, this might open new powerful therapeutic strategies.
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PMID:Fragile X syndrome: from molecular genetics to therapy. 1972 10

Costello syndrome (CS) is a developmental disorder characterized by postnatal reduced growth, facial dysmorphism, cardiac defects, mental retardation and skin and musculo-skeletal defects. CS is caused by HRAS germline mutations. In the majority of cases, mutations affect Gly(12) and Gly(13) and are associated with a relatively homogeneous phenotype. The same amino acid substitutions are well known as somatic mutations in human tumors and promote constitutive HRAS activation by impairing its GTPase activity. In a small number of cases with mild phenotype, a second class of substitutions involving codons 117 and 146 and affecting GTP/GDP binding has been described. Here, we report on the identification and functional characterization of two different three-nucleotide duplications resulting in a duplication of glutamate 37 (p.E37dup) associated with a homogeneous phenotype reminiscent of CS. Ectopic expression of HRAS(E37dup) in COS-7 cells resulted in enhanced growth factor-dependent stimulation of the MEK-ERK and phosphoinositide 3-kinase (PI3K)-AKT signaling pathways. Recombinant HRAS(E37dup) was characterized by slightly increased GTP/GDP dissociation, lower intrinsic GTPase activity and complete resistance to neurofibromin 1 GTPase-activating protein (GAP) stimulation due to dramatically reduced binding. Co-precipitation of GTP-bound HRAS(E37dup) by various effector proteins, however, was inefficient because of drastically diminished binding affinities. Thus, although HRAS(E37dup) is predominantly present in the active, GTP-bound state, it promotes only a weak hyperactivation of downstream signaling pathways. These findings provide evidence that the mildly enhanced signal flux through the MAPK and PI3K-AKT cascades promoted by these disease-causing germline HRAS alleles results from a balancing effect between a profound GAP insensitivity and inefficient binding to effector proteins.
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PMID:Duplication of Glu37 in the switch I region of HRAS impairs effector/GAP binding and underlies Costello syndrome by promoting enhanced growth factor-dependent MAPK and AKT activation. 1999 90

Many excitatory synapses express Group 1, or Gq coupled, metabotropic glutamate receptors (Gp1 mGluRs) at the periphery of their postsynaptic density. Activation of Gp1 mGluRs typically occurs in response to strong activity and triggers long-term plasticity of synaptic transmission in many brain regions, including the neocortex, hippocampus, midbrain, striatum, and cerebellum. Here we focus on mGluR-induced long-term synaptic depression (LTD) and review the literature that implicates Gp1 mGluRs in the plasticity of behavior, learning, and memory. Moreover, recent studies investigating the molecular mechanisms of mGluR-LTD have discovered links to mental retardation, autism, Alzheimer's disease, Parkinson's disease, and drug addiction. We discuss how mGluRs lead to plasticity of neural circuits and how the understanding of the molecular mechanisms of mGluR plasticity provides insight into brain disease.
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PMID:Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. 2018 50

Fragile X syndrome (FXS) results from deficiency of fragile X mental retardation protein (FMRP). FXS is the most common heritable form of mental retardation, and is associated with the occurrence of seizures. Factors responsible for initiating FXS-related hyperexcitability are poorly understood. Many protein-synthesis-dependent functions of group I metabotropic glutamate receptors (Gp1 mGluRs) are exaggerated in FXS. Gp1 mGluR activation can mobilize endocannabinoids (eCBs) in the hippocampus and thereby increase excitability, but whether FMRP affects eCBs is unknown. We studied Fmr1 knock-out (KO) mice lacking FMRP to test the hypothesis that eCB function is altered in FXS. Whole-cell evoked IPSCs (eIPSCs) and field potentials were recorded in the CA1 region of acute hippocampal slices. Three eCB-mediated responses were examined: depolarization-induced suppression of inhibition (DSI), mGluR-initiated eCB-dependent inhibitory short-term depression (eCB-iSTD), and eCB-dependent inhibitory long-term depression (eCB-iLTD). Low concentrations of a Gp1 mGluR agonist produced larger eCB-mediated responses in Fmr1 KO mice than in wild-type (WT) mice, without affecting DSI. Western blots revealed that levels of mGluR1, mGluR5, or cannabinoid receptor (CB1R) were unchanged in Fmr1 KO animals, suggesting that the coupling between mGluR activation and eCB mobilization was enhanced by FMRP deletion. The increased susceptibility of Fmr1 KO slices to eCB-iLTD was physiologically relevant, since long-term potentiation of EPSP-spike (E-S) coupling induced by the mGluR agonist was markedly larger in Fmr1 KO mice than in WT animals. Alterations in eCB signaling could contribute to the cognitive dysfunction associated with FXS.
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PMID:Enhanced endocannabinoid signaling elevates neuronal excitability in fragile X syndrome. 2041 Jan 24


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