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)

Fetal ischemia or hypoxia can lead to cerebral palsy, mental retardation and epilepsy. We propose that the production of nitric oxide and oxygen radicals by neurons when ischemic or hypoxic brain is reperfused may contribute to cerebral injury. Ischemia will depolarize neuronal membranes causing the synaptic discharge of the excitatory neurotransmitter glutamate, which in turn opens the voltage-dependent, N-methyl-D-aspartic acid-specific glutamate receptor/ionophore, allowing calcium to accumulate in the neuron. Calcium in turn activates an oxygen-dependent neuronal nitric oxide synthetase, which oxidizes arginine to produce nitric oxide (.NO) when oxygen is readmitted to brain by reperfusion. Nitric oxide reacts with the oxygen radical superoxide (O2-), also produced by reperfusion, to form peroxynitrite (ONOO-). Peroxynitrite can diffuse for several micrometers before decomposing to form the powerful and cytotoxic oxidants hydroxyl radical and nitrogen dioxide. The hypothesis is consistent with available evidence on the protective action of glutamate antagonists and of oxygen radical scavengers for limiting cerebral infarction following focal ischemia.
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PMID:The double-edged role of nitric oxide in brain function and superoxide-mediated injury. 167 55

Disorders of neuronal migration in cerebral cortex are associated with neurological impairments, including mental retardation and epilepsy. Their causes and pathophysiology remain largely unknown, however. In patients with Zellweger disease, a lethal panperoxisomal disorder, and in mice lacking the Pxr1 import receptor for peroxisomal matrix proteins, the absence of peroxisomes leads to abnormal neuronal migration. Analysis of Pxr1-/- mice revealed that the migration defect was caused by altered N-methyl-D-aspartate (NMDA) glutamate receptor-mediated calcium mobilization. This NMDA receptor dysfunction was linked to a deficit in platelet-activating factor, a phenomenon related to peroxisome impairment. These findings confirm NMDA receptor involvement in neuronal migration and suggest a link between peroxisome metabolism and NMDA receptor efficacy.
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PMID:Neuronal migration disorder in Zellweger mice is secondary to glutamate receptor dysfunction. 1097 40

Fetal alcohol syndrome (FAS) is the leading cause of mental retardation in western society. We investigated possible changes in glutamate receptor levels in neonatal animals following ethanol exposure using radioligand binding and western blot analysis. We used a vapor chamber to administer ethanol to neonatal Wistar rats 3 h a day from postnatal day (PND) 4-9. A separation control group was separated from their mothers for the same time and duration as the vapor treatment, while a normal control group was left to develop normally. Daily ethanol administrations resulted in decreased brain weight and body weight, as well as microencephaly (decreased brain:body weight ratio). Neither the affinity nor maximum binding of [(3)H]MK-801 (dizoclipine maleate) in the cortex of PND10 rats differed between treatment groups. Western blot analysis also failed to reveal any changes in NMDAR1, NMDAR2A, or NMDAR2B receptor levels. In contrast, the AMPA receptor subunit GluR1 was greatly reduced in vapor-treated pups compared with control pups, as revealed by western blot analysis. A similar reduction was found in westerns with an antibody recognizing the GluR2 and 4 subunits. These results indicate that ethanol reduces AMPA rather than NMDA receptors in the developing neocortex, possibly by blocking NMDA receptors during development.
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PMID:Neonatal ethanol exposure reduces AMPA but not NMDA receptor levels in the rat neocortex. 1203 20

Neuronal migration disorders (NMDs) can be associated with neurological dysfunction such as mental retardation, and clusters of disorganized cells (heterotopias) often act as seizure foci in medically intractable partial epilepsies. Methylazoxymethanol (MAM) treatment of pregnant rats results in neuronal heterotopias in offspring, especially in hippocampal area CA1. Although the neurons in dysplastic areas in this model are frequently hyperexcitable, the precise mechanisms controlling excitability remain unclear. Here, we used IR-DIC videomicroscopy and whole cell voltage-clamp techniques to test whether the potent anti-excitatory actions of neuropeptide Y (NPY) affected synaptic excitation of heterotopic neurons. We also compared several synaptic and intrinsic properties of heterotopic, layer 2-3 cortical, and CA1 pyramidal neurons, to further characterize heterotopic cells. NPY powerfully inhibited synaptic excitation onto normal and normotopic CA1 cells but was nearly ineffective on responses evoked in heterotopic cells from stimulation sites within the heterotopia. Glutamatergic synaptic responses on heterotopic cells exhibited a comparatively small, D-2-amino-5-phosphopentanoic acid-sensitive, N-methyl-D-aspartate component. Heterotopic neurons also differed from normal CA1 cells in postsynaptic membrane currents, possessing a prominent inwardly rectifying K(+) current sensitive to Cs(+) and Ba(2+), similar to neocortical layer 2-3 pyramidal cells. CA1 cells instead had a prominent Cs(+)- and 4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride-sensitive I(h) and negligible inward rectification, unlike heterotopic cells. Thus heterotopic CA1 cells appear to share numerous physiological similarities with neocortical neurons. The lack of NPY's effects on intra-heterotopic inputs, the small contribution of I(h), and abnormal glutamate receptor function, may all contribute to the lowered threshold for epileptiform activity observed in hippocampal heterotopias and could be important factors in epilepsies associated with NMDs.
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PMID:NPY sensitivity and postsynaptic properties of heterotopic neurons in the MAM model of malformation-associated epilepsy. 1242 9

To explore the hypothesis that L-phenylalanine (L-Phe) depresses glutamatergic synaptic transmission and thus contributes to brain dysfunction in phenylketonuria (PKU), the effects of L-Phe on spontaneous and miniature excitatory postsynaptic currents (s/mEPSCs) in rat and mouse hippocampal and cerebrocortical cultured neurons were studied using the patch-clamp technique. L-Phe depressed the amplitude and frequency of both N-methyl-D-aspartate (NMDA) and non-NMDA components of glutamate receptor (GluR) s/mEPSCs. The IC(50) of L-Phe to inhibit non-NMDAR mEPSC frequency was 0.98 +/- 0.13 mM, a brain concentration seen in classical PKU. In contrast, D-Phe had a significantly smaller effect, whereas L-leucine, an amino acid that competes with L-Phe for brain transporter, had no effect on mEPSCs. Unlike GluR s/mEPSCs, GABA receptor mIPSCs were not attenuated by L-Phe. A high extracellular concentration of glycine prevented the attenuation by L-Phe of NMDAR current, activated by exogenous agonist, and of NMDAR s/mEPSC amplitude, but not of NMDAR s/mEPSC frequency. On the other hand, L-Phe significantly depressed non-NMDAR current activated by low but not high concentrations of exogenous agonists. Glycine-independent attenuation of NMDAR s/mEPSC frequency suggests decreased presynaptic glutamate release caused by L-Phe, whereas decreased amplitudes of NMDAR and non-NMDAR s/mEPSCs are consistent with competition of L-Phe for the glycine- and glutamate-binding sites of NMDARs and non-NMDARs, respectively. The finding that GluR activity is significantly depressed at conditions characteristic of classical PKU indicates a potentially important contribution of impaired GluR function to PKU-related mental retardation and provides important insights into the potential physiological consequences of impaired GluR function.
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PMID:L-phenylalanine selectively depresses currents at glutamatergic excitatory synapses. 1264 85

A 1-year-8-month-old patient developed cerebellar ataxia following a prodromal infection. Despite initial diagnosis of acute cerebellar ataxia, his symptoms lasted for more than 30 days. High-dose intravenous immunoglobulin and steroid pulse therapy failed to ameliorate his cerebellar symptoms, which fluctuated in association with infections. At the age of 3 years and 8 months, he had mental retardation with cerebellar symptoms. Findings of MR imaging and single photon emission computed tomography were normal. Neuron-specific enolase of cerebrospinal fluid (CSF) ranged from 10.4-17.6 ng/ml, correlating with the cerebellar symptoms. Serum and CSF anti-glutamate receptor delta 2 antibodies were detected in the serum and CSF. We diagnosed him as having chronic cerebellitis associated with anti-glutamate receptor delta 2 antibody.
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PMID:[A case of chronic cerebellitis with anti-glutamate receptor delta 2 antibody]. 1473 66

Fragile X syndrome is caused by the absence of the mRNA-binding protein Fragile X mental retardation protein (FMRP), which may play a role in activity-regulated localization and translation of mRNA in dendrites and at synapses. We investigated whether neuronal activity and glutamatergic signals regulate trafficking of FMRP and its encoding Fmr1 mRNA into dendrites or at synapses. Using high-resolution fluorescence and digital imaging microscopy in cultured hippocampal neurons, FMRP and Fmr1 mRNA were localized in granules throughout dendrites and within spines. KCl depolarization rapidly increased FMRP and Fmr1 mRNA levels in dendrites. Metabotropic glutamate receptor (mGluR) activation, in particular mGluR5 activation, was necessary for localization of FMRP into dendrites. Blockade of either PKC or internal calcium prevented mGluR-dependent localization of both FMRP and Fmr1 mRNA in dendrites. The activity-dependent localization of FMRP was not dependent on protein synthesis. Fluorescence recovery after photobleaching analysis of live neurons transfected with enhanced green fluorescent protein-FMRP revealed increased granule trafficking in response to KCl depolarization. In contrast to its dendritic localization, mGluR activation diminished FMRP, but not Fmr1 mRNA, localization at synapses. These results demonstrate regulation of FMRP and Fmr1 mRNA trafficking in dendrites and synapses in response to specific glutamatergic signals.
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PMID:Metabotropic glutamate receptor activation regulates fragile x mental retardation protein and FMR1 mRNA localization differentially in dendrites and at synapses. 1502 57

We have identified truncating mutations in the human DLG3 (neuroendocrine dlg) gene in 4 of 329 families with moderate to severe X-linked mental retardation. DLG3 encodes synapse-associated protein 102 (SAP102), a member of the membrane-associated guanylate kinase protein family. Neuronal SAP102 is expressed during early brain development and is localized to the postsynaptic density of excitatory synapses. It is composed of three amino-terminal PDZ domains, an src homology domain, and a carboxyl-terminal guanylate kinase domain. The PDZ domains interact directly with the NR2 subunits of the NMDA glutamate receptor and with other proteins responsible for NMDA receptor localization, immobilization, and signaling. The mutations identified in this study all introduce premature stop codons within or before the third PDZ domain, and it is likely that this impairs the ability of SAP102 to interact with the NMDA receptor and/or other proteins involved in downstream NMDA receptor signaling pathways. NMDA receptors have been implicated in the induction of certain forms of synaptic plasticity, such as long-term potentiation and long-term depression, and these changes in synaptic efficacy have been proposed as neural mechanisms underlying memory and learning. The disruption of NMDA receptor targeting or signaling, as a result of the loss of SAP102, may lead to altered synaptic plasticity and may explain the intellectual impairment observed in individuals with DLG3 mutations.
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PMID:Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation. 1518 69

Fragile X (FRAX) syndrome is a common inherited form of mental retardation resulting from the lack of fragile X mental retardation protein (FMRP) expression. The consequences of FMRP absence in the mechanism underlying mental retardation are unknown. Here, we tested the hypothesis that glutamate receptor (GluR) expression might be altered in FRAX syndrome. Initial in situ hybridization and Western blotting experiments did not reveal differences in mRNA levels and protein expression of AMPA and NMDA subunits and metabotropic glutamate subtype 5 (mGlu5) receptors between control and Fmr1 knock-out (KO) mice during postnatal development. However, a detergent treatment (1% Triton X-100) revealed a selective reduction of mGlu5 receptor expression in the detergent-insoluble fraction of synaptic plasma membranes (SPMs) from KO mice, with no difference in the expression of NR2A, GluR1, GluR2/3, GluR4, and Homer proteins. mGlu5 receptor expression was also lower in Homer immunoprecipitates from Fmr1 KO SPMs. Homer, but not NR2A, mGlu5, and GluR1, was found to be less tyrosine phosphorylated in Fmr1 KO than control mice. Our data indicate that, in FRAX syndrome, a reduced number of mGlu5 receptors are tightly linked to the constituents of postsynaptic density and, in particular, to the constitutive forms of Homer proteins, with possible consequent alterations in synaptic plasticity.
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PMID:A reduced number of metabotropic glutamate subtype 5 receptors are associated with constitutive homer proteins in a mouse model of fragile X syndrome. 1619 81

Fragile X syndrome (FXS), a form of human mental retardation, is caused by loss of function mutations in the fragile X mental retardation gene (FMR1). The protein product of FMR1, fragile X mental retardation protein (FMRP) is an RNA-binding protein and may function as a translational suppressor. Metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) in hippocampal area CA1 is a form of synaptic plasticity that relies on dendritic protein synthesis. mGluR-LTD is enhanced in the mouse model of FXS, Fmr1 knockout (KO) mice, suggesting that FMRP negatively regulates translation of proteins required for LTD. Here we examine the synaptic and cellular mechanisms of mGluR-LTD in KO mice and find that mGluR-LTD no longer requires new protein synthesis, in contrast to wild-type (WT) mice. We further show that mGluR-LTD in KO and WT mice is associated with decreases in AMPA receptor (AMPAR) surface expression, indicating a similar postsynaptic expression mechanism. However, like LTD, mGluR-induced decreases in AMPAR surface expression in KO mice persist in protein synthesis inhibitors. These results are consistent with recent findings of elevated protein synthesis rates and synaptic protein levels in Fmr1 KO mice and suggest that these elevated levels of synaptic proteins are available to increase the persistence of LTD without de novo protein synthesis.
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PMID:Metabotropic receptor-dependent long-term depression persists in the absence of protein synthesis in the mouse model of fragile X syndrome. 1645 52


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