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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has become increasingly clear that the development and maintenance of synaptic connectivity patterns in the central and peripheral nervous system are not only based on the formation of synapses but include the selective elimination of synaptic subpopulations. Synaptic remodeling and elimination apparently also play a key role in the specification of neuronal connections during ontogenesis of the neocortex in various species. At least three types of synapse elimination have been demonstrated until now, i.e. physiological cell death of synaptically connected neurons, synaptic disconnection and lysosomal degradation, predominantly of presynaptic elements. Occurrence of different elimination types appears to depend on (1) whether the presynaptic or postsynaptic element induces the synaptic reorganization and (2) whether or not the neuron inducing the synapse elimination survives. The same type of synapse elimination may be seen during normal development and under pathological conditions. Factors inducing mental retardation may then either retard synapse formation or interfere with the process of synapse removal. In order to undergo plastic changes in synaptic connections, neurons may respond to exogenous factors such as lack of trophic factors or sensitivity for them (e.g. NGF), long-lasting changes in neuronal activity (e.g. due to drug application or sensory deprivation), hormonal influences (e.g. thyroxin or sexual hormones), learning conditions, or lesions (partial deafferentation and axotomy). The neurons, in turn, may change their responsiveness to exogenous stimuli by inducing synaptic reorganisation.
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PMID:Synaptic remodelling and elimination as integral processes of synaptogenesis. 831 96

Williams syndrome (SW) is a rare (2-5/100,000) genetic human disorder characterised by a typical facies and mental retardation with a deficit in the visuo-spatial cognitive function and a relative preservation of linguistic abilities. This syndrome also includes morphological anomalies and metabolic-functional impairments, likely deficits in the pattern of brain ontogenesis. Neuropsychological and somatic features of the SW individuals are illustrated, and the correspondent genetic bases, recently identified, are presented. The possible role of NGF (nerve growth factor), a particular neurotrophin involved in the development of brain cholinergic system and the associated behavioural functions, in the aetiology of the typical mental retardation of SW patients, is critically discussed. Prospect of researches, including the identification of potential neurobiological markers and the definition of appropriate cognitive profiles of the SW, in order to precociously diagnose this syndrome, and a more thorough investigation of factors affecting phenotypic expression of this genetically determined pathological condition, are reviewed.
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PMID:[Williams syndrome: a window to the development of cognitive and neural processes]. 947 Feb 50

Williams syndrome (WS) is a rare (2-5/100,000) genetic human disorder characterised by a typical facies and mental retardation with a deficit in the visuospatial cognitive function and a relative preservation of linguistic abilities in general, and spoken language in particular. This syndrome also includes morphological anomalies, metabolic functional impairments, and likely deficits in the pattern of brain ontogenesis. The genetic basis of WS, recently identified, are presented. A cognitive profile of the WS individuals is defined and compared to Down syndrome (DS) and autism cognitive profiles. Neuroanatomical features of WS, including a reduction in brain volume, preservation of cerebellum and frontal lobes, and a reduction of posterior cortical systems, are described. The possible role of NGF (nerve growth factor)--a neurotrophin involved in the development of brain cholinergic systems and the associated behavioural functions--in the aetiology of the typical mental retardation of WS patients, is critically discussed. Future research avenues, including the identification of potential neurobiological markers in order to precociously diagnose this syndrome, are reviewed.
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PMID:[Williams syndrome]. 1064 54

1. Fragile X syndrome, the most common form of inherited mental retardation, is caused by the lack or dysfunction of fragile X mental retardation protein (FMRP). The 1304N mutation in the RNA-binding domain of FMRP results in an exceptionally severe form of mental retardation. 2. We have investigated the subcellular localization of FMRP and its 1304N-mutated form in cultured hippocampal neurons and PC12 cells, using immunofluorescence microscopy. In PC12 cells, FMRP was predominantly localized to the cytoplasm and also to the processes after differentiation by NGF. 3. In cultured hippocampal neurons, granular labeling was detected along the neuronal processes. 4. Double-labeling with synaptophysin antibody revealed FMRP at synaptic sites in neurons. 5. The 1304N mutation did not appear to affect the transport of FMRP to dendrites or its localization at synaptic sites. Thus, FMRP is a synaptic protein and the severe phenotype observed in the patient with the 1304N mutation is not produced by alterations in dendritic transport.
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PMID:Subcellular localization of fragile X mental retardation protein with the I304N mutation in the RNA-binding domain in cultured hippocampal neurons. 1144 Jan 96

Myotonic dystrophy (DM) is a dominant neuromuscular disorder caused by the expansion of trinucleotide CTG repeats in the 3-untranslated region (3'-UTR) of the MtPK gene. Although DM-associated mental retardation suggests that neuronal functions are disturbed by the expansion mutation, the effect of this alteration in neuronal cells has not been approached. In this study we established stable transfectans of PC12 neuronal cell line expressing the reporter gene CAT alone (empty-vector clone) or fused to the MtPK 3'-UTR with 5, 60, or 90 CTG repeats (CTG5, CTG60, and CTG90 clones, respectively). CTG90 cells exhibited a suppression of NGF-induced neuronal differentiation while empty-vector, CTG5 and CTG60 clones differentiated normally. CTG90 cells displayed normal activation of early differentiation markers, ERK1/2, but the up-regulation of the late marker MAP2 was dramatically reduced. Our neuronal cell system provides the first information of how the mutant MtPK 3'-UTR mRNA affects neuronal functions.
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PMID:Expanded CTG repeats inhibit neuronal differentiation of the PC12 cell line. 1215 Sep 45

Mental retardation is a main feature of the congenital form of myotonic dystrophy (DM1), however, the molecular mechanisms underlying the central nervous system symptoms of DM1 are poorly understood. We have established a PC12 cell line-based model expressing the DM1 expanded CUG repeats (CTG90 cells) to analyze the effects of this mutation on neuronal functions. Previously, we have reported that CTG90 cells displayed impaired NGF-induced neuronal differentiation. Because disruption of normal expression of the microtubule associated protein tau and neuronal aggregates of hyperphosphorylated tau have been associated with DM1, this study analyzes the behavior of tau in the CTG90 cells. Several alterations of tau were observed in the PC12 cells that express expanded CUG repeats, including a subtle but reproducible reduction in the expression of the tau mRNA splicing isoform containing exon 10, decreased expression of tau and hyperphosphorylation of both tau and high molecular weight tau as well as abnormal nuclear localization of tau phosphorylated at Ser396/404. Interestingly, phosphorylation regulates negatively the activity of tau as microtubule-associated protein. In addition, impaired activity of the Akt/GSK3beta pathway, which phosphorylates tau, was also identified in the CTG90 cells. Besides tau phosphorylation, the Akt/GSK3beta signaling pathway regulates other key processes of PC12 cells, such as apoptosis and neuronal differentiation. Our results indicate that defective neuronal differentiation exhibited by the PC12 cells expressing expanded CUG repeats could be the result of combinatory effects derived from the altered behavior of tau and the impaired activation of the Akt/GSK3beta signaling pathway.
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PMID:Myotonic dystrophy expanded CUG repeats disturb the expression and phosphorylation of tau in PC12 cells. 1686 53

PC12 cells are a well-known model of parasympathetic neurons. They have also been used to study the dynamics of heterologously expressed fragile X mental retardation (FMRP) granule trafficking down neurites. Here, we demonstrate that undifferentiated and differentiated PC12 cells harbor endogenous FMRP-containing granules. These granules are not stress granules because they do not associate with an authentic stress granule marker protein T-cell internal antigen 1 (TIA-1). Treatment with sodium arsenite induces stress granule formation in undifferentiated and differentiated PC12 cells. In NGF-treated cells, FMRP-containing stress granules are observed in the soma, neurites and growth cones by co-immunostaining with anti-TIA-1 antibody. These data demonstrate that all three microdomains respond similarly to oxidative stress. Nevertheless, we find significantly less co-localization of FMRP and TIA-1 and FMRP and its homologs in the neurites of differentiated PC12 cells treated with sodium arsenite than in the soma or growth cones. The heterogeneity of these granules suggests that FMRP has multiple roles in neurites.
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PMID:Oxidative stress reveals heterogeneity of FMRP granules in PC12 cell neurites. 1691 43

Tuberous sclerosis complex (TSC) is an autosomal dominant inherited disorder characterized by benign tumors (hamartomas) in various organs. The brain is one of the most severely affected organs with neuropsychiatric disorders including epilepsy, mental retardation and autism. The identification of TSC genes (TSC1 and TSC2) and their gene products (hamartin and tuberin, respectively), revealed that they function together as a complex. However, mutations in TSC2 are often accompanied by more severe neurologic deficits. Here, we show that hamartin and tuberin play different roles in NGF-treated cultured neuronal cells PC12h. The level of hamartin in PC12h cells was slightly and gradually increased, while those of tuberin rapidly increased upon NGF-induced neuronal differentiation in PC12h cells. Antisense for TSC1 (TSC1-AS) or TSC2-AS reduced expression of hamartin or tuberin, respectively, and enhanced S-phase of cell cycle in PC12h cells. Suppression of hamartin significantly enhanced neurite outgrowth after NGF-treatment in PC12h cells, while suppression of tuberin inhibited neurite outgrowth. Expression of activated V14RhoA reverted TSC1-AS induced abnormal neurite development. These results suggest that loss of hamartin results in abnormal neurite elongation through Rho inactivation in NGF-treated PC12h cells, which may be associated with the neurological manifestations of TSC.
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PMID:Antisense suppression of TSC1 gene product, hamartin, enhances neurite outgrowth in NGF-treated PC12h cells. 1737 23

The Down syndrome critical region (DSCR) on Chromosome 21 contains many genes whose duplication may lead to the major phenotypic features of Down syndrome and especially the associated mental retardation. However, the functions of DSCR genes are mostly unknown and their possible involvement in key brain developmental events still largely unexplored. In this report we show that the protein TTC3, encoded by one of the main DSCR candidate genes, physically interacts with Citron kinase (CIT-K) and Citron N (CIT-N), two effectors of the RhoA small GTPase that have previously been involved in neuronal proliferation and differentiation. More importantly, we found that TTC3 levels can strongly affect the NGF-induced differentiation of PC12 cells, by a CIT-K-dependent mechanism. Indeed, TTC3 overexpression leads to strong inhibition of neurite extension, which can be reverted by CIT-K RNAi. Conversely, TTC3 knockdown stimulates neurite extension in the same cells. Finally, we find that Rho, but not Rho kinase, is required for TTC3 differentiation-inhibiting activity. Our results suggest that the TTC3-RhoA-CIT-K pathway could be a crucial determinant of in vivo neuronal development, whose hyperactivity may result in detrimental effects on the normal differentiation program.
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PMID:The Down syndrome critical region protein TTC3 inhibits neuronal differentiation via RhoA and Citron kinase. 1748 80

Exposure to ethanol during development induces severe brain damage resulting in a number of CNS dysfunctions including microencephaly and mental retardation in humans and in laboratory animals. The most vulnerable period to ethanol neurotoxicity coincides with the peak of brain growth spurt. Recently, neurotrophic factors and/or their signal transduction pathways have been reported as a potential relevant target for the developmental neurotoxicity of ethanol. The present studies were designed to investigate the effects of ethanol given in various developmental phases during the brain growth spurt in rats. Rat pups were assigned to the three treatment groups and treated with 5 g/kg of ethanol for three days, on postnatal days (PND) 2-4, 6-8 or 13-15. Whole brain weights were reduced only in the PND 6-8 group concurrently with the reduction of GDNF mRNA in cortex in this group. BDNF mRNA expression was reduced in both the PND 6-8 and 13-15 groups, while mRNA expressions of NT-3 and NGF were unchanged in all three groups. Phospho-Akt level was mostly reduced in the PND 6-8 group. Both phospho-MAPK and p-70S6 kinase levels were decreased in all groups whereas no changes were observed in either phospho-PKCzeta or CREB level. The phosphorylation of Akt was immediately inhibited after single administration of ethanol, and its inhibition was correlated with variations in blood ethanol concentration. These findings suggest that GDNF and the phosphorylation of Akt play a possible key role in the ethanol-induced developmental neurotoxicity.
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PMID:Effects of postnatal ethanol exposure at different developmental phases on neurotrophic factors and phosphorylated proteins on signal transductions in rat brain. 1835 98


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