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Query: UMLS:C0917816 (mental retardation)
 15,867 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malformations of cortical development are increasingly recognized in association with severe epileptic syndromes, neuropsychological disorders and mental retardation. Several clinical and experimental studies suggest that functional consequences of cortical dysplasias are not restricted to the area of the dysplastic lesion but also involve remote brain regions. In the present study cortical malformations were induced in newborn rats at day of birth by intracerebral injection of the glutamatergic agonist ibotenate. The resulting cytoarchitectonic lesion associates neuronal depopulation of deep cortical layers, ectopic neurons in superficial layers and sulcus formation, mimicking human polymicrogyria and migration disorders. Electrophysiological recordings of evoked field potentials in slice preparations of adult animals reveal hyperexcitability in widespread cortical regions surrounding the dysplasia. Low-intensity stimulation induced epileptiform activity consisting of long-lasting, multiphasic and N-methyl-D-aspartate-dependent field responses. They appeared with high variability as all-or-none events. These widespread changes in excitability were not observed in sham-operated animals with small superficial ectopias but intact deep cortical layers, indicating that focal loss of these layers induces extended alterations in cortical connectivity and imbalance of excitation and inhibition. Restricted zones of increased excitability were also found in the forelimb and hindlimb representation cortex in sham-operated and control animals, demonstrating that this activity has to be considered as an intrinsic property of specific cortical areas. Deoxyglucose autoradiography showed that the widespread hyperexcitability in ibotenate-injected animals was not accompanied by alterations in glucose metabolism, although in the area of structural abnormality a typical metabolic pattern was found, revealing an increased glucose uptake in layer I. Hypometabolism as described for many types of human dysplastic lesions was not observed. This difference between the experimental and clinical data may be due to the absence of behavioral seizures in this model. However, it can be hypothesized that in patients with developmental malformations, additional pathogenic factors contribute to the manifestation of seizure disorders.
Cereb Cortex
PMID:Excitability changes and glucose metabolism in experimentally induced focal cortical dysplasias. 982 83

Effects of thyroid hormone on development of the brain have been documented for over a century. Although in many respects the hypothyroid brain appears morphologically normal, functional impairments include mental retardation, ataxia and spasticity. Keyed by the discovery of nuclear receptors for thyroid hormone that function as transcription factors, recent work has examined the mechanism of thyroid hormone action in brain development. The prediction that gene expression regulated by thyroid hormone is important for mediating brain development has spurred the search for thyroid hormone-responsive genes. Here we review some of the identified genes whose expression patterns correlate with the functional deficits observed in the hypothyroid brain. Recently identified thyroid hormone-responsive genes include synaptotagmin-related gene 1 (Srg1), a putative mediator of synaptic structure and/or activity, and hairless, a transcriptional cofactor that may influence the expression of other thyroid hormone-responsive genes.
Cereb Cortex 2000 Oct
PMID:Thyroid hormone action in neural development. 1100 44

Dendritic abnormalities are the most consistent anatomical correlates of mental retardation (MR). Earliest descriptions included dendritic spine dysgenesis, which was first associated with unclassified MR, but can also be found in genetic syndromes associated with MR. Genetic disorders with well-defined dendritic anomalies involving branches and/or spines include Down, Rett and fragile-X syndromes. Cytoarchitectonic analyses also suggest dendritic pathology in Williams and Rubinstein-Taybi syndromes. Dendritic abnormalities appear to have syndrome-specific pathogenesis and evolution, which correlate to some extent with their cognitive profile. The significance of dendritic pathology in synaptic circuitry and the role of animal models in the study of MR-associated dendritic abnormalities are also discussed. Finally, a model of genotype to neurologic phenotype pathway in MR, centered in dendritic abnormalities, is postulated.
Cereb Cortex 2000 Oct
PMID:Dendritic anomalies in disorders associated with mental retardation. 1100 49

Many syndromes associated with mental retardation (MR) are characterized by cortical dendritic anomalies. Despite their morphological similarity, these changes appear to involve different stages of dendritic development. The neuronal cytoskeleton, which includes microfilaments, neurofilaments and microtubules, is essential for these developmental processes. Levels and phosphorylation of microtubule-associated proteins (MAPs), which stabilize microtubules, seem to determine different stages of dendritic formation with certain MAPs (e.g. MAP-2) appearing to mediate the effects of external modulators upon these processes. Early studies on neuronal cytoskeleton in MR, which have shown a selective reduction in MAP-2 expression, have focused on Rett syndrome (RS). Here, by a semiquantitative immunohistochemical analysis of the pericentral cortex, we examine the contribution of specific neuronal populations to these changes in cytoskeletal proteins. Decreased MAP-2 staining in RS was more marked in layers V-VI, while increased nonphosphorylated neurofilament immunoreactivity was found in layers II-III in RS. Age-related increases in dendritic MAP-2 immunoreactivity in layers V-VI were also absent in RS. The specificity of these cytoskeletal protein changes, their significance for RS pathogenesis and plasticity, as well as their implications for other MR-associated disorders, are also discussed.
Cereb Cortex 2000 Oct
PMID:Dendritic cytoskeletal protein expression in mental retardation: an immunohistochemical study of the neocortex in Rett syndrome. 1100 50

Fragile-X syndrome is the most common single-gene inherited form of mental retardation. Morphological studies suggest a possible failure of the synapse maturation process. Cerebral cortical spine morphology in fragile-X syndrome and in a knockout mouse model of it appears immature, with long, thin spines much more common than the stubby and mushroom-shaped spines more characteristic of normal development. In human fragile-X syndrome there is also a higher density of spines along dendrites, suggesting a possible failure of synapse elimination. While variously misshapen spines are characteristic of a number of mental retardation syndromes, the overabundance of spines seen in fragile-X syndrome is unusual. Taken with evidence of neurotransmitter activation of the synthesis of the fragile-X protein (FMRP) at synapses in vitro and evidence for behaviorally induced FMRP expression in vivo, and with evidence compatible with a role for FMRP in regulating the synthesis of other proteins, it is possible that FMRP serves as an 'immediate early protein' at the synapse that orchestrates aspects of synaptic development and plasticity.
Cereb Cortex 2000 Oct
PMID:Dendritic spine structural anomalies in fragile-X mental retardation syndrome. 1100 54

Fragile-X, the main cause of inherited human mental retardation is associated with the absence of a recently identified fragile-X mental retardation protein (FMRP). Mice in which this protein is lacking due to a knockout (KO) mutation are reported to express altered dendritic spines on their cortical neurons compared with wild type (WT) controls. We have used tissue-cultured neurons to examine differences in morphology and synaptic connectivity between WT and FMRP-deficient mice. Hippocampal neurons taken from KO mice and grown in culture for 3 weeks have shorter dendrites and fewer dendritic spines than their WT counterparts. Also, KO cells tend to express fewer functional synaptic connections, which develop more slowly and produce smaller excitatory synaptic currents than WT controls. These observations may have important implications for the understanding of mental retardation associated with the absence of FMRP.
Cereb Cortex 2000 Oct
PMID:FMRP involvement in formation of synapses among cultured hippocampal neurons. 1100 55

Type I lissencephaly is a cortical malformation disorder characterized by disorganized cortical layers and gyral abnormalities and associated with severe cognitive impairment and epilepsy. The exact pathophysiological mechanisms underlying the epilepsy and mental retardation in this and related disorders remain unknown. Two genes, LIS1 and doublecortin, have both been shown to be mutated in a large proportion of cases of type I lissencephaly and a milder allelic disorder, subcortical laminar heterotopia (SCLH). Studying the protein products of these genes and the biochemical pathways in which they belong is likely to yield important information concerning both normal and abnormal cortical development. The relationships between the LIS1 and Doublecortin proteins are not yet well defined, but both are believed to play a critical role in cortical neuronal migration. Lis1 is expressed from very early development in the mouse and in both proliferating cells and post-mitotic neurons of the cortex. This protein is likely to have multiple functions since it is a subunit of the enzyme platelet-activating factor acetylhydrolase, which degrades platelet activating factor, and has also been shown to be involved in microtubule dynamics, potentially influencing nuclear migration through its interaction with the dynein motor protein complex. Doublecortin on the other hand is exclusively expressed in post-mitotic neurons and is developmentally regulated. In young developing neurons Doublecortin has a specific subcellular localization at the ends of neuritic and leading processes. This localization, combined with our previous data showing that it is a microtubule-associated protein and that it interacts with adapter complexes involved in vesicle trafficking, suggests a role in the growth of neuronal processes, downstream of directional or guidance signals. The observations summarized here favor the suggestion that whereas LIS1 may play a role in nuclear migration, Doublecortin is instead restricted to functions at the leading edge of the cell.
Cereb Cortex 2003 Jun
PMID:Doublecortin functions at the extremities of growing neuronal processes. 1276 37

Subcortical band heterotopia (SBH) or double cortex is associated with significant impairments in neocortical function including mental retardation and epilepsy. Mutant alleles of DCX in humans typically cause SBH in females and lissencephaly in males, whereas Dcx null mutations in mice neither disrupt neocortical neuronal migration nor cause SBH formation. In utero RNA interference (RNAi) of Dcx in rats, in contrast, creates an animal model of SBH. Possible explanations for the discrepancies in results following loss of Dcx function include species differences and/or differences between RNAi knockdown and genetic deletion. We have carried out a series of in utero RNAi experiments to investigate possible species differences between rat and mouse to determine the molecular specificity of RNAi against Dcx and to identify the cellular constituents of SBH in the rat model. In utero RNAi in the rat consistently leads to both the formation of SBH and laminar displacement of transfected cells in normotopic cortex, whereas the same treatment in mouse fails to induce SBH but does create laminar displacement. Induction of SBH and impaired radial migration following RNAi against Dcx is rescued by overexpression of Dcx. Thus, both disruptions induced by RNAi are specific to interference of Dcx. SBHs contain transfected pyramidal cells as well as nontransfected cell types, including neocortical interneurons and glia. Together these results indicate that there is a species difference between rat and mouse with respect to RNAi-induced SBH formation and that SBH formation involves the recruitment of several unaltered cell types.
Cereb Cortex 2006 Sep
PMID:Heterotopia formation in rat but not mouse neocortex after RNA interference knockdown of DCX. 1629 2

In human, neuronal migration disorders are commonly associated with developmental delay, mental retardation, and epilepsy. We describe here a new mouse mutant that develops a heterotopic cortex (HeCo) lying in the dorsolateral hemispheric region, between the homotopic cortex (HoCo) and subcortical white matter. Cross-breeding demonstrated an autosomal recessive transmission. Birthdating studies and immunochemistry for layer-specific markers revealed that HeCo formation was due to a transit problem in the intermediate zone affecting both radially and tangentially migrating neurons. The scaffold of radial glial fibers, as well as the expression of doublecortin is not altered in the mutant. Neurons within the HeCo are generated at a late embryonic age (E18) and the superficial layers of the HoCo have a correspondingly lower cell density and layer thickness. Parvalbumin immunohistochemistry showed the presence of gamma-aminobutyric acidergic cells in the HeCo and the mutant mice have a lowered threshold for the induction of epileptic seizures. The mutant showed a developmental delay but, in contrast, memory function was relatively spared. Therefore, this unique mouse model resembles subcortical band heterotopia observed in human. This model represents a new and rare tool to better understand cortical development and to investigate future therapeutic strategies for refractory epilepsy.
Cereb Cortex 2009 Mar
PMID:Characterization of the HeCo mutant mouse: a new model of subcortical band heterotopia associated with seizures and behavioral deficits. 1856 29

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.
Cereb Cortex 2009 Jul
PMID:Downregulation of tonic GABAergic inhibition in a mouse model of fragile X syndrome. 1938 37


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