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)

The amino acid proline has long been suspected to serve as a modulator of synaptic transmission in the mammalian brain, but no such function has been identified. The selective expression of high affinity proline transport by a subset of glutamate pathways suggested that proline might play a role in synaptic transmission at these sites. This idea was tested with use of one such pathway, the Schaffer collateral-commissural projection to CA1 pyramidal cells of the rat hippocampus. Proline enhanced the initial slope of the field EPSP without affecting axonal excitability or the magnitude of paired-pulse facilitation. Proline-induced potentiation far outlasted the period of proline application and required the activation of NMDA receptors. Proline enhanced Schaffer collateral-commissural synaptic transmission even when the connections between areas CA1 and CA3 had been interrupted. Potentiation was observed with a proline concentration normally present in human CSF (3 microM). A concentration typical of CSF in persons with the genetic disorder hyperprolinemia type II (30 microM) produced a somewhat greater effect. Occlusion experiments suggested that proline-induced potentiation and tetanus-induced long-term potentiation utilize largely distinct transduction mechanisms. Proline-induced potentiation could be blocked by a prior high frequency stimulus, whether or not the stimulus evoked long-term potentiation. These results suggest that endogenous extracellular proline regulates the basal function of some glutamate synapses by maintaining them in a partially potentiated state. They may also facilitate understanding of the seizures and/or mental retardation associated with genetic disorders of proline metabolism.
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PMID:Proline-induced potentiation of glutamate transmission. 925 26

Ornithine Transcarbamylase (OTC) is a key urea cycle enzyme. Congenital OTC deficiencies in humans result in hyperammonemia and a spectrum of neurological symptoms including hypotonia, seizures and mental retardation. Neuropathologic evaluation reveals cerebral atrophy, ventricular enlargement and Alzheimer type II astrocytosis. Using an animal model of congenital OTC deficiency, the sparse fur (spf) mouse, recent studies have revealed significant alterations of cholinergic, serotoninergic and glutamatergic neurotransmitter systems. Possible pathophysiologic mechanisms responsible for neuronal cell loss in OTC deficiency include a deficit in cerebral energy metabolism, and glutamate excitotoxicity. Therapy continues to rely on alternative substrate administration including sodium benzoate and sodium phenylacetate. Experimental evidence suggests that acetyl-L-carnitine and glutamate (NMDA) receptor antagonists could be potentially useful therapeutic agents. Liver transplantation is effective in many patients and recent experimental studies using adenoviral vectors suggest that gene therapy may ultimately be useful in the treatment of congenital OTC deficiency.
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PMID:Ornithine transcarbamylase deficiency: pathogenesis of the cerebral disorder and new prospects for therapy. 934 66

Disturbances in cell migration are heterogenic disorders of brain development commonly associated with epilepsy and mental retardation. We report a 45-year-old oligophrenic man with defect of lower limbs and family history of mental retardation who died because of brainstem hemorrhage. At post-mortem and histopathological examination, complex brain malformation characterized by bilateral periventricular heterotopia, cortical dysgenesia, partial agenesia of corpus callosum and thin-walled blood vessels was found. Immunohistochemical examination revealed the presence of fibronectin, collagen IV and laminin in wall of pathological vessels. Cyclooxygenase-2 (COX-2) expression in neurons within heterotopias and dysgenic cortex was negative. It may indicate their maturity and indirectly, normal activity of postsynaptic NMDA receptors that explains absence of epileptic attacks in our patient. The presence of COX-2-negative neurons and compounds of basal lamina in fetal-like vessels within heterotopias and dysgenic cortex, suggests that these probably initially immature structures became mature during 45 years of patient's life.
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PMID:Early ontogenic disturbances in cell migration in mentally disabled adult. 1122 Jun 89

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

Hyperammonemia is mainly found in hepatic encephalopathy and in genetic defects of the urea cycle or other pathways of the intermediary metabolism. Clinically a difference has to be made between chronic moderate hyperammonemia and acutely increased concentrations. Pathogenetic mechanisms of ammonia toxicity to the brain are partly unraveled. In some animal models confounding variables, such as the reduced intake of food and amino acid imbalance due to liver insufficiency, do not allow to establish unequivocal causal relationships between the ammonia concentration and measured effects. In chronic moderate hyperammonemia an increased flux through the serotonin pathway is a key factor. It is caused by an increased transport of large neutral amino acids (including tryptophan) through the blood-brain barrier, accentuated by the imbalance of plasma amino acids in hepatic insufficiency. It is stimulated by D- or L-glutamine. Evidence is presented showing that a functioning gamma-glutamyl cycle (glutathione formation) is a prerequisite. In acute hyperammonemia involvement of NMDA receptors, glutamate, NO and cGMP plays an additional role. In hyperammonemic crises the increased cerebral blood flow leads to brain edema; factors discussed here are increased osmolytes in astrocytes and serotoninergic activity. Recent data indicate that axonal development is affected by ammonia and can be normalized in vitro by creatine supplementation in developing mixed brain cell aggregate cultures, thus reviving the old hypothesis of the impact of hyperammonemia on energy metabolism in the developing brain that could cause mental retardation.
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PMID:Mechanisms of hyperammonemia. 1224 Oct 9

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

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 syndrome is the most common form of inherited mental retardation and is caused by the loss of function of the Fragile X mental retardation protein (FMRP). FMRP is an RNA binding protein thought to play a key role in protein synthesis-dependent synaptic plasticity. The regulation of FMRP expression itself is also likely to be an important control point in this process. Here we used dark-reared/light-exposed rats to determine the role of experience in regulating FMRP levels in the visual cortex. We find that FMRP levels increase in the cell bodies and dendrites of visual cortical neurons after as little as 15 min of light exposure. Remarkably, FMRP expression in these neurons returns to baseline levels by 30 min of light exposure. These changes were post-transcriptional because the FMR1 mRNA levels remained constant over this time period. A transient increase in FMRP levels was also observed in synaptic fractions prepared from visual cortices of light-exposed animals. In contrast, alpha-calcium/calmodulin-dependent kinase II expression showed a sustained upregulation under these conditions. Finally, the increase in FMRP expression was inhibited by blockade of NMDA receptors. This tight temporal-spatial regulation suggests that FMRP plays a dynamic role in a distinct epoch of experience-dependent synaptic plasticity.
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PMID:Visual experience regulates transient expression and dendritic localization of fragile X mental retardation protein. 1556 73

Many forms of mental retardation and cognitive disability are associated with abnormalities in dendritic spine morphology. Visualization of spines using live-imaging techniques provides convincing evidence that spine morphology is altered in response to certain forms of LTP-inducing stimulation. Thus, information storage at the cellular level appears to involve changes in spine morphology that support changes in synaptic strength produced by certain patterns of synaptic activity. Because the structure of a spine is determined by its underlying actin cytoskeleton, there has been much effort to identify signaling pathways linking synaptic activity to control of actin polymerization. This review, part of the TINS Synaptic Connectivity series, discusses recent studies that implicate EphB and NMDA receptors in the regulation of actin-binding proteins through modulation of Rho family small GTPases.
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PMID:Spine architecture and synaptic plasticity. 1580 52

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


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