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)

After dealing with the biochemistry of tryptophan metabolism the most important results obtained in humans are presented. Special emphasis is given to the hereditary defects of tryptophan metabolism associated with mental retardation and convulsions due to lack of pyridoxine. The author's findings demonstrate the existence of a hereditary disturbance of the tryptophan metabolism via kynurenine in a certain part of oligophrenic patients. This metabolic defect can be controlled by high doses of vitamin B6. Furthermore investigations conducted with a view to interpreting these results are discussed, especially the determination of kynureninase activity, serotonin blood levels and pyridine nucleotide synthesis.
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PMID:[Tryptophan metabolism and oligophrenia (author's transl)]. 14 46

Fragile X Syndrome is a leading heritable cause of mental retardation that results from the loss of FMR1 gene function. Studies in mouse and Drosophila model organisms have been critical in understanding many aspects of the loss of function of the FMR1 gene in the human syndrome. Here, we establish that the zebrafish is a useful model organism for the study of the human fragile X syndrome and can be used to examine phenotypes that are difficult or inaccessible to observation in other model organisms. Using morpholino knockdown of the fmr1 gene, we observed abnormal axonal branching of Rohon-Beard and trigeminal ganglion neurons and guidance and defasciculation defects in the lateral longitudinal fasciculus. We demonstrate that this axonal branching defect can be rescued by treatment with MPEP [2-methyl-6-(phenylethynyl) pyridine]. This is consistent with an interaction between mGluR signalling and fmr1 function in neurite morphogenesis. We also describe novel findings of abnormalities in the abundance of trigeminal ganglion neurons and of craniofacial abnormalities apparently due to dysmorphic cartilage formation. These abnormalities may be related to a role for fmr1 in neural crest cell specification and possibly in migration.
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PMID:Contribution of mGluR and Fmr1 functional pathways to neurite morphogenesis, craniofacial development and fragile X syndrome. 1706 72

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

Fragile X syndrome (FXS), a common inherited form of mental retardation, is caused by the functional absence of the fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates the translation of specific mRNAs at synapses. Altered synaptic plasticity has been described in a mouse FXS model. However, the mechanism by which the loss of FMRP alters synaptic function, and subsequently causes the mental impairment, is unknown. Here, in cultured hippocampal neurons, we used siRNAs against Fmr1 to demonstrate that a reduction of FMRP in dendrites leads to an increase in internalization of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunit, GluR1, in dendrites. This abnormal AMPAR trafficking was caused by spontaneous action potential-driven network activity without synaptic stimulation by an exogenous agonist and was rescued by 2-methyl-6-phenylethynyl-pyridine (MPEP), an mGluR5-specific inverse agonist. Because AMPAR internalization depends on local protein synthesis after mGluR5 stimulation, FMRP, a negative regulator of translation, may be viewed as a counterbalancing signal, wherein the absence of FMRP leads to an apparent excess of mGluR5 signaling in dendrites. Because AMPAR trafficking is a driving process for synaptic plasticity underlying learning and memory, our data suggest that hypersensitive AMPAR internalization in response to excess mGluR signaling may represent a principal cellular defect in FXS, which may be corrected by using mGluR antagonists.
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PMID:Fragile X mental retardation protein deficiency leads to excessive mGluR5-dependent internalization of AMPA receptors. 1788 61

Fragile X syndrome (FXS), caused by silencing of the Fmr1 gene, is the most common form of inherited mental retardation. Epilepsy is reported to occur in 20-25% of individuals with FXS. However, no overall increased excitability has been reported in Fmr1 knockout (KO) mice, except for increased sensitivity to auditory stimulation. Here, we report that kindling increased the expressions of Fmr1 mRNA and protein in the forebrain of wild-type (WT) mice. Kindling development was dramatically accelerated in Fmr1 KO mice, and Fmr1 KO mice also displayed prolonged electrographic seizures during kindling and more severe mossy fiber sprouting after kindling. The accelerated rate of kindling was partially repressed by inhibiting N-methyl-D-aspartic acid receptor (NMDAR) with MK-801 or mGluR5 receptor with 2-methyl-6-(phenylethynyl)-pyridine (MPEP). The rate of kindling development in WT was not effected by MPEP, however, suggesting that FMRP normally suppresses epileptogenic signaling downstream of metabolic glutamate receptors. Our findings reveal that FMRP plays a critical role in suppressing limbic epileptogenesis and predict that the enhanced susceptibility of patients with FXS to epilepsy is a direct consequence of the loss of an important homeostatic factor that mitigates vulnerability to excessive neuronal excitation.
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PMID:Limbic epileptogenesis in a mouse model of fragile X syndrome. 1969 30

The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in anxiety, depression, pain, mental retardation, and addiction. The potent and selective noncompetitive mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP, 1) has been a critically important tool used to further elucidate the role of mGluR5 in these CNS disorders. In an effort to provide novel and structurally diverse selective mGluR5 antagonists, we previously described a set of analogues with moderate activity wherein the alkyne bond was replaced with an amide group. In the present report, extended series of both amide and alkyne-based ligands were synthesized. MGluR5 binding and functional data were obtained that identified (1) several novel alkynes with comparable affinities to 1 at mGluR5 (e.g., 10 and 20-23), but (2) most structural variations to the amide template were not well tolerated, although a few potent amides were discovered (e.g., 55 and 56). Several of these novel analogues show drug-like physical properties (e.g., cLogP range = 2-5) that support their use for in vivo investigation into the role of mGluR5 in CNS disorders.
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PMID:Structure-activity relationships comparing N-(6-methylpyridin-yl)-substituted aryl amides to 2-methyl-6-(substituted-arylethynyl)pyridines or 2-methyl-4-(substituted-arylethynyl)thiazoles as novel metabotropic glutamate receptor subtype 5 antagonists. 1944 53

Purines and pyrimidines, regarded for a long time only as building blocks for nucleic acid synthesis and intermediates in the transfer of metabolic energy, gained increasing attention since genetically determined aberrations in their metabolism were associated clinically with various degrees of mental retardation and/or unexpected and often devastating neurological dysfunction. In most instances the molecular mechanisms underlying neurological symptoms remain undefined. This suggests that nucleotides and nucleosides play fundamental but still unknown roles in the development and function of several organs, in particular central nervous system. Alterations of purine and pyrimidine metabolism affecting brain function are spread along both synthesis (PRPS, ADSL, ATIC, HPRT, UMPS, dGK, TK), and breakdown pathways (5NT, ADA, PNP, GCH, DPD, DHPA, TP, UP), sometimes also involving pyridine metabolism. Explanations for the pathogenesis of disorders may include both cellular and mitochondrial damage: e.g. deficiency of the purine salvage enzymes hypoxanthine-guanine phosphoribosyltransferase and deoxyguanosine kinase are associated to the most severe pathologies, the former due to an unexplained adverse effect exerted on the development and/or differentiation of dopaminergic neurons, the latter due to impairment of mitochondrial functions. This review gathers the presently known inborn errors of purine and pyrimidine metabolism that manifest neurological syndromes, reporting and commenting on the available hypothesis on the possible link between specific enzymatic alterations and brain damage. Such connection is often not obvious, and though investigated for many years, the molecular basis of most dysfunctions of central nervous system associated to purine and pyrimidine metabolism disorders are still unexplained.
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PMID:Neurological disorders of purine and pyrimidine metabolism. 2140 1

The most common cause of inherited mental retardation, fragile X syndrome, results from a triplet repeat expansion in the FMR1 gene and loss of the mRNA binding protein, fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group I metabotropic glutamate receptors (mGluRs) is enhanced. We previously proposed a mechanism whereby the audiogenic seizures exhibited by FMR1 null mice result from an imbalance in excitatory mGluR and inhibitory GABA(B) receptor (GABA(B)R) signaling (Mol Pharmacol 76:18-24, 2009). Here, we tested the mGluR5-positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB), the mGluR5 inverse agonist 2-methyl-6-(phenylethynyl)pyridine (MPEP), and GABA(B) receptor agonists, alone and in combination on receptor protein expression and audiogenic seizures in FMR1 mice. Single doses of MPEP (30 mg/kg), the GABA(B)R orthosteric agonist R-baclofen (1 mg/kg), or the GABA(B)R-positive allosteric modulator N,N'-dicyclopentyl-2-(methylthio)-5-nitro-4,6-pyrimidine diamine (GS-39783) (30 mg/kg), reduced the incidence of seizures. However, when administered subchronically (daily injections for 6 days), MPEP retained its anticonvulsant activity, whereas R-baclofen and GS-39783 did not. When administered at lower doses that had no effect when given alone, a single injection of MPEP plus R-baclofen also reduced seizures, but the effect was lost after subchronic administration. We were surprised to find that subchronic treatment with R-baclofen also induced tolerance to a single high dose of MPEP. These data demonstrate that tolerance develops rapidly to the antiseizure properties of R-baclofen alone and R-baclofen coadministered with MPEP, but not with MPEP alone. Our findings suggest that cross-talk between the G-protein signaling pathways of these receptors affects drug efficacy after repeated treatment.
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PMID:Subchronic administration and combination metabotropic glutamate and GABAB receptor drug therapy in fragile X syndrome. 2163 56

Amongst the many neurotransmitter systems causally linked to the expression of social behavior, glutamate appears to play a pivotal role. In particular, metabotropic glutamate 5 (mGlu5) receptors have received much attention as its altered function has been reported in several mouse models of autism spectrum disorders and mental retardation. Inhibition of the activity of mGlu5 receptors by means of genetic or pharmacological manipulations improved social deficits in some of these animal models. However, in normal wild-type (WT) mice, pharmacological blockade of mGlu5 receptors yielded inconsistent results. The aim of our study was to investigate the actual contribution of decreased or absent mGlu5 receptor function in sociability and anxiety-like behavior as well as to explore the impact of mGlu5 receptor ablation on the pattern of brain activation upon social exposure. Here we show that Grm5-/- mice display higher social preference indexes compared to age-matched WT mice in the three-chambered social task. However, this effect was accompanied by a decreased exploratory activity during the test and increased anxiety-like behavior. Contrary to mGlu5 receptor ablation, the mGlu5 receptor negative allosteric modulator 3-((2-methyl-1,4-thiazolyl)ethynyl)pyridine (MTEP) induced anxiolytic effects without affecting social preference in WT mice. By mapping c-Fos expression in 21 different brain regions known to be involved in social interaction, we detected a specific activation of the prefrontal cortex and dorsolateral septum in Grm5-/- mice following social interaction. C-Fos expression correlation-based network and graph theoretical analyses further suggested dysfunctional connectivity and disruption of the functional brain network generated during social interaction in Grm5-/- mice. The lack of mGlu5 receptors resulted in profound rearrangements of the functional impact of prefrontal and hippocampal regions in the social interaction network. In conclusion, this work reveals a complex contribution of mGlu5 receptors in sociability and anxiety and points to the importance of these receptors in regulating brain functional connectivity during social interaction.
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PMID:An Appraisal of the Influence of the Metabotropic Glutamate 5 (mGlu5) Receptor on Sociability and Anxiety. 3087 1