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)

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

Tuberous sclerosis complex (TSC) is a common hereditary disorder caused by mutations in either the TSC1 or TSC2 genes, and characterized by severe epilepsy, cerebral hamartomas and mental retardation. We have used rats that are heterozygous for an autosomal-dominant germline mutation in the TSC2 gene (TSC2+/- rats) to examine the consequences of TSC2 mutations for hippocampal synaptic plasticity. While basal synaptic transmission in the Schaffer collateral-CA1 synapse was not altered, paired-pulse plasticity was significantly enhanced in TSC2+/- rats (interpulse intervals 20-200 ms). Moreover, TSC2+/- rats exhibited a marked reduction of different forms of synaptic plasticity. Long-term potentiation (LTP) elicited following high-frequency tetanization of Schaffer collaterals was significantly decreased from 1.45 +/- 0.05-fold potentiation to 1.15 +/- 0.04 (measured after 60 min). This difference in LTP levels between TSC2+/- and wild-type rats also persisted in the presence of the gamma-aminobutyric acid (GABA)(A) receptor antagonist bicuculline. In addition to changed LTP, the level of long-term depression (LTD) elicited by different forms of low-frequency stimulation was significantly less in TSC2+/- rats. These results suggest that TSC2 mutations may cause hippocampal synapses to lose much of their potential for activity-dependent synaptic modification. An understanding of the underlying molecular pathways may suggest new therapeutic approaches aimed at inhibiting the development of the profound mental retardation in TSC.
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PMID:Impaired synaptic plasticity in a rat model of tuberous sclerosis. 1726 62

Fragile X syndrome (FXS) is a common form of mental retardation caused by the absence of functional fragile X mental retardation protein (FMRP). FXS is associated with elevated density and length of dendritic spines, as well as an immature-appearing distribution profile of spine morphologies in the neocortex. Mice that lack FMRP (Fmr1 knockout mice) exhibit a similar phenotype in the neocortex, suggesting that FMRP is important for dendritic spine maturation and pruning. Examination of Golgi-stained pyramidal cells in hippocampal subfield CA1 of adult Fmr1 knockout mice reveals longer spines than controls and a morphology profile that, while essentially opposite of that described in the Fmr1 knockout neocortex, appears similarly immature. This finding strongly suggests that FMRP is required for the processes of spine maturation and pruning in multiple brain regions and that the specific pathology depends on the cellular context.
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PMID:Hippocampal pyramidal cells in adult Fmr1 knockout mice exhibit an immature-appearing profile of dendritic spines. 1657 84

Loss of oligophrenin1 (OPHN1) function in human causes X-linked mental retardation associated with cerebellar hypoplasia and, in some cases, with lateral ventricle enlargement. In vitro studies showed that ophn1 regulates dendritic spine through the control of Rho GTPases, but its in vivo function remains unknown. We generated a mouse model of ophn1 deficiency and showed that it mimics the ventricles enlargement without affecting the cerebellum morphoanatomy. The ophn1 knock-out mice exhibit behavioral defects in spatial memory together with impairment in social behavior, lateralization, and hyperactivity. Long-term potentiation and mGluR-dependent long-term depression are normal in the CA1 hippocampal area of ophn1 mutant, whereas paired-pulse facilitation is reduced. This altered short-term plasticity that reflects changes in the release of neurotransmitters from the presynaptic processes is associated with normal synaptic density together with a reduction in mature dendritic spines. In culture, inactivation of ophn1 function increases the density and proportion of immature spines. Using a conditional model of loss of ophn1 function, we confirmed this immaturity defect and showed that ophn1 is required at all the stages of the development. These studies show that, depending of the context, ophn1 controls the maturation of dendritic spines either by maintaining the density of mature spines or by limiting the extension of new filopodia. Altogether, these observations indicate that cognitive impairment related to OPHN1 loss of function is associated with both presynaptic and postsynaptic alterations.
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PMID:Loss of X-linked mental retardation gene oligophrenin1 in mice impairs spatial memory and leads to ventricular enlargement and dendritic spine immaturity. 1772 57

Gq-coupled, M1 muscarinic acetylcholine receptors (mAChRs) facilitate hippocampal learning, memory, and synaptic plasticity. M1 mAChRs induce long-term synaptic depression (LTD), but little is known about the underlying mechanisms of mAChR-dependent LTD and its link to cognitive function. Here, we demonstrate that chemical activation of M1 mAChRs induces LTD in hippocampal area CA1, which relies on rapid protein synthesis, as well as the extracellular signal-regulated kinase and mammalian target of rapamycin translational activation pathways. Synaptic stimulation of M1 mAChRs, alone, or together with the Gq-coupled glutamate receptors (mGluRs), also results in protein synthesis-dependent LTD. New proteins maintain mAChR-dependent LTD through a persistent decrease in surface AMPA receptors. mAChRs stimulate translation of the RNA-binding protein, Fragile X mental retardation protein (FMRP) and FMRP target mRNAs. In mice without FMRP (Fmr1 knock-out), a model for human Fragile X syndrome mental retardation (FXS), both mGluR- and mAChR-dependent protein synthesis and LTD are affected. Our results reveal that multiple Gq-coupled receptors converge on a common protein synthesis-dependent LTD mechanism, which is aberrant in FXS. These findings suggest novel therapeutic strategies for FXS in the form of mAChR antagonists.
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PMID:Multiple Gq-coupled receptors converge on a common protein synthesis-dependent long-term depression that is affected in fragile X syndrome mental retardation. 1795 5

Mutations in regulators and effectors of the Rho GTPases underlie various forms of mental retardation (MR). Among them, oligophrenin-1 (OPHN1), which encodes a Rho-GTPase activating protein, was one of the first Rho-linked MR genes identified. Upon characterization of OPHN1 in hippocampal brain slices, we obtained evidence for the requirement of OPHN1 in dendritic spine morphogenesis and neuronal function of CA1 pyramidal neurons. Organotypic hippocampal brain slice cultures are commonly used as a model system to investigate the morphology and synaptic function of neurons, mainly because they allow for the long-term examination of neurons in a preparation where the gross cellular architecture of the hippocampus is retained. In addition, maintenance of the trisynaptic circuitry in hippocampal slices enables the study of synaptic connections. Today, a multitude of gene transfer methods for postmitotic neurons in brain slices are available to easily manipulate and scrutinize the involvement of signaling molecules, such as Rho GTPases, in specific cellular processes in this system. This chapter covers techniques detailing the preparation and culturing of organotypic hippocampal brain slices, as well as the production and injection of lentivirus into brain slices.
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PMID:Characterization of oligophrenin-1, a RhoGAP lost in patients affected with mental retardation: lentiviral injection in organotypic brain slice cultures. 1837 70

Evidence is accumulating that Rab3A plays a key role in neurotransmitter release and synaptic plasticity. Recently mutations in the catalytic subunit p130 and the noncatalytic subunit p150 of Rab3 GTPase-activating protein were found to cause Warburg Micro syndrome and Martsolf syndrome, respectively, both of which exhibit mental retardation. We have found that loss of p130 in mice results in inhibition of Ca2+-dependent glutamate release from cerebrocortical synaptosomes and alters short-term plasticity in the hippocampal CA1 region, probably through the accumulation of the GTP-bound form of Rab3A. Here, we describe the procedures for the measurement of the GTP-bound pool of Rab3A with pull-down assay using mouse brains and the biochemical method for the measurement of glutamate release from mouse synaptosomes.
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PMID:Analysis on the emerging role of Rab3 GTPase-activating protein in Warburg Micro and Martsolf syndrome. 1841 45

Tuberous sclerosis is a single-gene disorder caused by heterozygous mutations in the TSC1 (9q34) or TSC2 (16p13.3) gene and is frequently associated with mental retardation, autism and epilepsy. Even individuals with tuberous sclerosis and a normal intelligence quotient (approximately 50%) are commonly affected with specific neuropsychological problems, including long-term and working memory deficits. Here we report that mice with a heterozygous, inactivating mutation in the Tsc2 gene (Tsc2(+/-) mice) show deficits in learning and memory. Cognitive deficits in Tsc2(+/-) mice emerged in the absence of neuropathology and seizures, demonstrating that other disease mechanisms are involved. We show that hyperactive hippocampal mammalian target of rapamycin (mTOR) signaling led to abnormal long-term potentiation in the CA1 region of the hippocampus and consequently to deficits in hippocampal-dependent learning. These deficits included impairments in two spatial learning tasks and in contextual discrimination. Notably, we show that a brief treatment with the mTOR inhibitor rapamycin in adult mice rescues not only the synaptic plasticity, but also the behavioral deficits in this animal model of tuberous sclerosis. The results presented here reveal a biological basis for some of the cognitive deficits associated with tuberous sclerosis, and they show that treatment with mTOR antagonists ameliorates cognitive dysfunction in a mouse model of this disorder.
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PMID:Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. 1856 33

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

Germline mutations in SPRED1, a negative regulator of Ras, have been described in a neurofibromatosis type 1 (NF1)-like syndrome (NFLS) that included learning difficulties in some affected individuals. NFLS belongs to the group of phenotypically overlapping neuro-cardio-facial-cutaneous syndromes that are all caused by germ line mutations in genes of the Ras/mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) pathway and that present with some degree of learning difficulties or mental retardation. We investigated hippocampus-dependent learning and memory as well as synaptic plasticity in Spred1(-/-) mice, an animal model of this newly discovered human syndrome. Spred1(-/-) mice show decreased learning and memory performance in the Morris water maze and visual-discrimination T-maze, but normal basic neuromotor and sensory abilities. Electrophysiological recordings on brain slices from these animals identified defects in short- and long-term synaptic hippocampal plasticity, including a disequilibrium between long-term potentiation (LTP) and long-term depression in CA1 region. Biochemical analysis, 4 h after LTP induction, demonstrated increased ERK-phosphorylation in Spred1(-/-) slices compared with those of wild-type littermates. This indicates that deficits in hippocampus-dependent learning and synaptic plasticity induced by SPRED1 deficiency are related to hyperactivation of the Ras/ERK pathway.
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PMID:Spred1 is required for synaptic plasticity and hippocampus-dependent learning. 1911 78


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