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

Down syndrome (DS), affecting 1/700 live births, is the major genetic cause of mental retardation (MR), a cognitive disorder with hard impact on public health. DS brain is characterized by a reduced cerebellar volume and number of granular cells, defective cortical lamination and reduced cortical neurons, malformed dendritic trees and spines, and abnormal synapses. These neurological alterations, also found in trisomic mouse models, result from gene-dosage effects of Human Chromosome 21 (HC21) on the expression of critical developmental genes. HC21 sequencing, mouse ortholog gene identification and DS mouse model generation lead to determine HC21 gene functions and the effects of protein-dosage alterations in neurodevelopmental and metabolic pathways in DS individuals. Trisomic brain transcriptome of DS patients and trisomic mouse models identified some molecular changes determined by gene-overdosage and associated dysregulation of some disomic gene expression in DS brains. These transcriptional variations cause developmental alterations in neural patterning and signal transduction pathways that may lead to defective neuronal circuits responsible for the pathogenesis of MR in DS. Recently, the first altered molecular pathway responsible of some DS phenotypes, including neurological and cognitive disorders has been identified. In this pathway, two critical HC21 genes (DYRK1A and DSCR1) act synergistically to control the phosphorylation levels of NFATc and NFATc-regulated gene expression. Interestingly, the NFATc mice show neurological dysfunctions similar to those seen in DS patients and trisomic mouse models. Treatment of DS mouse model Ts65Dn with GABA(A) antagonists allowed post-drug rescue of cognitive defects, indicating a hopeful direction in clinical therapies for MR in children with DS.
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PMID:Mental retardation and associated neurological dysfunctions in Down syndrome: a consequence of dysregulation in critical chromosome 21 genes and associated molecular pathways. 1793 68

The endocannabinoid system, including its receptors (CB(1) and CB(2)), endogenous ligands ('endocannabinoids'), synthesising and degrading enzymes, as well as transporter molecules, has been detected from the earliest stages of embryonic development and throughout pre- and postnatal development. In addition, the endocannabinoids, notably 2-arachidonyl glycerol, are also present in maternal milk. During three distinct developmental stages (i.e. embryonic implantation, prenatal brain development and postnatal suckling), the endocannabinoid system appears to play an essential role for development and survival. Thus, during early pregnancy, successful embryonic passage through the oviduct and implantation into the uterus both require critical enzymatic control of optimal anandamide levels at the appropriate times and sites. During foetal life, the cannabinoid CB(1) receptor plays a major role in brain development, regulating neural progenitor differentiation into neurones and glia and guiding axonal migration and synaptogenesis. Postnatally, CB(1) receptor blockade interferes with the initiation of milk suckling in mouse pups, by inducing oral motor weakness, which exposes a critical role for CB(1) receptors in the initiation of milk suckling by neonates, possibly by interfering with innervation of the tongue muscles. Manipulating the endocannabinoid system by pre- and/or postnatal administration of cannabinoids or maternal marijuana consumption, has significant, yet subtle effects on the offspring. Thus, alterations in the dopamine, GABA and endocannabinoid systems have been reported while enhanced drug seeking behaviour and impaired executive (prefrontal cortical) function have also been observed. The relatively mild nature of the disruptive effects of prenatal cannabinoids may be understood in the framework of the intricate timing requirements and frequently biphasic effects of the (endo)cannabinoids. In conclusion, the endocannabinoid system plays several key roles in pre- and postnatal development. Future studies should further clarify the mechanisms involved and provide a better understanding of the adverse effects of prenatal exposure, in order to design strategies for the treatment of conditions such as infertility, mental retardation and failure-to-thrive.
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PMID:Multiple roles for the endocannabinoid system during the earliest stages of life: pre- and postnatal development. 1842 4

The aristaless-related homeobox (ARX) gene has been implicated in a wide spectrum of disorders ranging from phenotypes with severe neuronal migration defects, such as lissencephaly, to mild forms of X-linked mental retardation without apparent brain abnormalities. To better understand its role in corticogenesis, we used in utero electroporation to knock down or overexpress ARX. We show here that targeted inhibition of ARX causes cortical progenitor cells to exit the cell cycle prematurely and impairs their migration toward the cortical plate. In contrast, ARX overexpression increases the length of the cell cycle. In addition, we report that RNA interference-mediated inactivation of ARX prevents cells from acquiring multipolar morphology in the subventricular and intermediate zones, resulting in decreased neuronal motility. In contrast, ARX overexpression appears to promote the development of tangentially oriented processes of cells in the subventricular and intermediate zones and affects radial migration of pyramidal neurons. We also demonstrate that the level of ARX expression is important for tangential migration of GABA-containing interneurons, because both inactivation and overexpression of the gene impair their migration from the ganglionic eminence. However, our data suggest that ARX is not directly involved in GABAergic cell fate specification. Overall, these results identify multiple and distinct cell-autonomous roles for ARX in corticogenesis.
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PMID:Cell-autonomous roles of ARX in cell proliferation and neuronal migration during corticogenesis. 1850 41

Individuals with homozygous deficiency in cystathionine-beta-synthase (CBS) develop high levels of homocysteine in plasma, a condition known as homocysteinuria. Mental retardation ensues with death in teens; the heterozygous live normally but develop vascular dementia and Alzheimer's disease (AD) in later part of life. The treatment with muscimol, a gamma amino butyric acid receptor-A (GABA(A)) agonist, mitigates the AD syndrome and vascular dementia. We tested the hypothesis that homocysteine (Hcy) antagonizes the GABA(A) receptor and behaves as an excitotoxic neurotransmitter that causes blood brain barrier (BBB) permeability and vascular dementia. The BBB permeability was measured by infusing Evan's blue dye (2% in saline 5 ml/kg concentration) in CBS-/+, GABA(A)-/-, CBS-/+/GABA(A)-/- double knockout, CBS-/+ mice treated with muscimol and wild type (WT) mice. Matrix Metalloproteinase (MMP-2, MMP-9), Tissue Inhibitor of Matrix Metalloproteinase (TIMP-3, TIMP-4), collagen-III and elastin levels were measured in whole brain by Western blot. These results suggested an increase in Evan's blue permeability: CBS-/+<GABA(A)-/-<CBS-/+/GABA(A)-/- compared to WT mice. Interestingly, in CBS-/+ mice treated with muscimol, BBB permeability was significantly decreased compared with the CBS-/+ group. There was a decrease in the TIMP-4 protein expression level, whereas the TIMP-3 level increased in CBS-/+, GABA(A)-/-, and CBS-/+/GABA(A)-/- mice compared to the WT. MMP-2 and MMP-9 expression significantly increased in all the groups compared to the wild type. The results suggested that Hcy caused cerebral interstitial remodeling in brain by distorting the extracellular matrix, thus increasing the blood brain permeability; treatment with muscimol mitigated BBB permeability.
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PMID:GABAA receptor agonist mitigates homocysteine-induced cerebrovascular remodeling in knockout mice. 1854 46

Clustering of inhibitory gamma-aminobutyric acid(A) (GABA(A)) and glycine receptors at synapses is thought to involve key interactions between the receptors, a "scaffolding" protein known as gephyrin and the RhoGEF collybistin. We report the identification of a balanced chromosomal translocation in a female patient presenting with a disturbed sleep-wake cycle, late-onset epileptic seizures, increased anxiety, aggressive behavior, and mental retardation, but not hyperekplexia. Fine mapping of the breakpoint indicates disruption of the collybistin gene (ARHGEF9) on chromosome Xq11, while the other breakpoint lies in a region of 18q11 that lacks any known or predicted genes. We show that defective collybistin transcripts are synthesized and exons 7-10 are replaced by cryptic exons from chromosomes X and 18. These mRNAs no longer encode the pleckstrin homology (PH) domain of collybistin, which we now show binds phosphatidylinositol-3-phosphate (PI3P/PtdIns-3-P), a phosphoinositide with an emerging role in membrane trafficking and signal transduction, rather than phosphatidylinositol 3,4,5-trisphosphate (PIP3/PtdIns-3,4,5-P) as previously suggested in the "membrane activation model" of gephyrin clustering. Consistent with this finding, expression of truncated collybistin proteins in cultured neurons interferes with synaptic localization of endogenous gephyrin and GABA(A) receptors. These results suggest that collybistin has a key role in membrane trafficking of gephyrin and selected GABA(A) receptor subtypes involved in epilepsy, anxiety, aggression, insomnia, and learning and memory.
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PMID:A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression, and mental retardation. 1861 34

The absence of fragile X mental retardation protein results in the fragile X syndrome (FXS), a common form of mental retardation associated with attention deficit, autistic behavior, and epileptic seizures. The phenotype of FXS is reproduced in fragile X mental retardation 1 (fmr1) knockout (KO) mice that have region-specific altered expression of some gamma-aminobutyric acid (GABA(A)) receptor subunits. However, little is known about the characteristics of GABAergic inhibition in the subiculum of these animals. We employed patch-clamp recordings from subicular pyramidal cells in an in vitro slice preparation. In addition, semiquantitative polymerase chain reaction and western blot experiments were performed on subiculum obtained from wild-type (WT) and KO mice. We found that tonic GABA(A) currents were downregulated in fmr1 KO compared with WT neurons, whereas no significant differences were observed in phasic GABA(A) currents. Molecular biology analysis revealed that the tonic GABA(A) receptor subunits alpha5 and delta were underexpressed in the fmr1 KO mouse subiculum compared with WT. Because the subiculum plays a role in both cognitive functions and epileptic disorders, we propose that altered tonic inhibition in this structure contributes to the behavioral deficits and epileptic activity seen in FXS patients. This conclusion is in line with evidence implicating tonic GABA(A) inhibition in learning and memory.
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PMID:Downregulation of tonic GABAergic inhibition in a mouse model of fragile X syndrome. 1938 37

ATRX, a chromatin remodeling protein of the Snf2 family, participates in diverse cellular functions including regulation of gene expression and chromosome alignment during mitosis and meiosis. Mutations in the human gene cause alpha thalassemia mental retardation, X-linked (ATR-X) syndrome, a rare disorder characterized by severe cognitive deficits, microcephaly and epileptic seizures. Conditional inactivation of the Atrx gene in the mouse forebrain leads to neonatal lethality and defective neurogenesis manifested by increased cell death and reduced cellularity in the developing neocortex and hippocampus. Here, we show that Atrx-null forebrains do not generate dentate granule cells due to a reduction in precursor cell number and abnormal migration of differentiating granule cells. In addition, fewer GABA-producing interneurons are generated that migrate from the ventral telencephalon to the cortex and hippocampus. Staining for cleaved caspase 3 demonstrated increased apoptosis in both the hippocampal hem and basal telencephalon concurrent with p53 pathway activation. Elimination of the tumor suppressor protein p53 in double knock-out mice rescued cell death in the embryonic telencephalon but only partially ameliorated the Atrx-null phenotypes at birth. Together, these findings show that ATRX deficiency leads to p53-dependent neuronal apoptosis which is responsible for some but not all of the phenotypic consequences of ATRX deficiency in the forebrain.
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PMID:Neuronal death resulting from targeted disruption of the Snf2 protein ATRX is mediated by p53. 1902 49

After our initial discovery of reduced expression of several subunits of the GABA(A) receptor in two different animal models for fragile X syndrome, a frequent form of inherited mental retardation, we analyzed further components of the GABAergic pathway. Interestingly, we found a down regulation of many additional elements of the GABA signalling system, strengthening our hypothesis of involvement of the GABAergic pathway in the pathophysiology of fragile X syndrome. This is of special interest with regard to new therapeutic opportunities for treatment of this disorder. Remarkably, under expression was predominantly observed in cortex, although some elements of the GABAergic system that are expressed presynaptically or in the glial cells were also down regulated in the cerebellum. Additionally, we assessed the GABAergic system in expanded CGG-repeat mice, a model for fragile X associated tremor/ataxia syndrome (FXTAS). This late onset neurodegenerative disorder occurs in carriers of the fragile X premutation (55-200 CGG repeats) and is completely distinct (from both clinical and molecular pathogenic perspectives) from the neurodevelopmental disorder fragile X syndrome. Here we found upregulation of many components of the GABAergic system in cerebellum, but not in cortex. This finding is consistent with the cerebellar phenotype of FXTAS patients and has implications for the mechanism causative of differential gene expression.
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PMID:Expression of the GABAergic system in animal models for fragile X syndrome and fragile X associated tremor/ataxia syndrome (FXTAS). 1907 Jun 6

In human patients, cortical dysplasia produced by Doublecortin (DCX) mutations lead to mental retardation and intractable infantile epilepsies, but the underlying mechanisms are not known. DCX(-/-) mice have been generated to investigate this issue. However, they display no neocortical abnormality, lessening their impact on the field. In contrast, in utero knockdown of DCX RNA produces a morphologically relevant cortical band heterotopia in rodents. On this preparation we have now compared the neuronal and network properties of ectopic, overlying, and control neurons in an effort to identify how ectopic neurons generate adverse patterns that will impact cortical activity. We combined dynamic calcium imaging and anatomical and electrophysiological techniques and report now that DCX(-/-)EGFP(+)-labeled ectopic neurons that fail to migrate develop extensive axonal subcortical projections and retain immature properties, and most of them display a delayed maturation of GABA-mediated signaling. Cortical neurons overlying the heterotopia, in contrast, exhibit a massive increase of ongoing glutamatergic synaptic currents reflecting a strong reactive plasticity. Neurons in both experimental fields are more frequently coactive in coherent synchronized oscillations than control cortical neurons. In addition, both fields displayed network-driven oscillations during evoked epileptiform burst. These results show that migration disorders produce major alterations not only in neurons that fail to migrate but also in their programmed target areas. We suggest that this duality play a major role in cortical dysfunction of DCX brains.
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PMID:Abnormal network activity in a targeted genetic model of human double cortex. 1914 32

Infantile spasms syndrome (ISS) is a catastrophic pediatric epilepsy with motor spasms, persistent seizures, mental retardation, and in some cases, autism. One of its monogenic causes is an insertion mutation [c.304ins (GCG)(7)] on the X chromosome, expanding the first polyalanine tract of the interneuron-specific transcription factor Aristaless-related homeobox (ARX) from 16 to 23 alanine codons. Null mutation of the Arx gene impairs GABA and cholinergic interneuronal migration but results in a neonatal lethal phenotype. We developed the first viable genetic mouse model of ISS that spontaneously recapitulates salient phenotypic features of the human triplet repeat expansion mutation. Arx((GCG)10+7) ("Arx plus 7") pups display abnormal spasm-like myoclonus and other key EEG features, including multifocal spikes, electrodecremental episodes, and spontaneous seizures persisting into maturity. The neurobehavioral profile of Arx mutants was remarkable for lowered anxiety, impaired associative learning, and abnormal social interaction. Laminar decreases of Arx+ cortical interneurons and a selective reduction of calbindin-, but not parvalbumin- or calretinin-expressing interneurons in neocortical layers and hippocampus indicate that specific classes of synaptic inhibition are missing from the adult forebrain, providing a basis for the seizures and cognitive disorder. A significant reduction of calbindin-, NPY (neuropeptide Y)-expressing, and cholinergic interneurons in the mutant striatum suggest that dysinhibition within this network may contribute to the dyskinetic motor spasms. This mouse model narrows the range of critical pathogenic elements within brain inhibitory networks essential to recreate this complex neurodevelopmental syndrome.
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PMID:A triplet repeat expansion genetic mouse model of infantile spasms syndrome, Arx(GCG)10+7, with interneuronopathy, spasms in infancy, persistent seizures, and adult cognitive and behavioral impairment. 2012 36


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