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)

This study investigated the actions of proline on CA1 hippocampal pyramidal cells with use of slice preparations. Bath-applied L-proline first induced these cells to fire multiple orthodromic population spikes in response to a single stimulus and then blocked their response to both orthodromic and antidromic stimulation. These effects could be explained by postsynaptic depolarization followed by depolarization block. Grease-gap studies confirmed that L-proline depolarizes CA1 pyramidal cells. D-Proline was inactive in these tests. Excitatory amino acid antagonists reduced depolarizing responses to proline and N-methyl-D-aspartate (NMDA) in parallel. Mn2+ failed to attenuate proline-evoked depolarizations at concentrations that substantially inhibited synaptic transmission, but at a higher concentration it reduced responses to both proline and NMDA. These results suggest that proline depolarized CA1 pyramidal cells mainly by activating postsynaptic NMDA receptors. The neuroexcitatory and neurotoxic actions of proline in the hippocampus may contribute to the seizures and mental retardation associated with hyperprolinemia.
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PMID:NMDA receptor-mediated depolarizing action of proline on CA1 pyramidal cells. 135 8

Stem cell factor (SCF) promotes the growth of multilineage hematopoietic cells. SCF is a product of the steel (Sl) locus of the mouse, and it is a ligand for the c-kit proto-oncogene receptor. Previous studies have investigated the distribution of SCF mRNA in developing and adult tissues of the rat, including the brain. However, there have been conflicting reports on the distribution of SCF mRNA in adult rat brain. Specially noteworthy was one report of the absence of SCF mRNA in adult hippocampus, while another group reported the presence of that mRNA in the dentate gyrus of the hippocampus. We conducted this study to determine the precise localization of SCF mRNA in adult brain, and were especially interested in determining whether that mRNA is localized in adult hippocampus. We used in situ hybridization histochemistry to demonstrate that the gene encoding SCF is actively expressed in neuron-like cells in various regions of adult rat brain. Our data show that SCF mRNA is present in neuron-like cells in the thalamus, cerebral cortex, cerebellum, and hippocampus, particularly in the dentate gyrus, but also in CA1, CA2, and CA3. We did not localize SCF mRNA in glia-like cells. Dyskeratosis congenita is a severe human disorder, associated with dyskeratosis, anemia, and mental retardation. It has been postulated that dyskeratosis congenita is due to a deficiency in SCF function. It is unknown why patients with dyskeratosis congenita suffer from mental retardation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Localization of stem cell factor mRNA in adult rat hippocampus. 748 32

The binding of the muscarinic acetylcholine antagonist quinuclinidylbensilate to its specific receptors was measured by quantitative autoradiography in the brain of the HPH-5 mouse, a phenylalanine hydroxylase-deficient mouse mutant, as a model for human PKU. Three types of response to a hyperphenylalaninemic condition were observed: no effect as in the putamen; a gradual decrease over time such as in several areas of the cerebral cortex and the hippocampus; a transient increase, followed by a decrease, such as in the frontal area of the cerebral cortex. Of particular significance is the effect on the CA1 and CA3 layer of the hippocampus, since this structure has been implicated in the acquisition and storage of long-term memory. Hyperphenylalaninemia leads to a decrease in neurotransmitter receptor density and, therefore, to a decrease in connectivity, which may form the basis for the mental retardation in this condition.
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PMID:Loss of neurotransmitter receptors by hyperphenylalaninemia in the HPH-5 mouse brain. 776 46

Previous studies on the effect of hyperphenylalaninaemia on the development of the muscarinic acetylcholine receptor in the cerebrum of the rat, using alpha-methylphenylalanine-induced hyperphenylalaninaemia, have shown a gradual and steady decrease in the number of binding sites for this neurotransmitter. The HPH-5 mouse, a phenylalanine hydroxylase mutant, can be hyperphenylalaninaemic without the use of a hydroxylase inhibitor. By employing quantitative autoradiography using [3H]quinuclinidylbenzilate to label muscarinic acetylcholine receptors, a refined analysis of this decrease in neurotransmitter binding sites can be made. The decrease was confirmed and is therefore due to the hyperphenylalaninaemia per se and not to the use of the inhibitor. Various areas of the brain reacted differently to hyperphenylalaninaemia, from no change (putamen) to a gradual decrease (external layer of the olfactory bulb, parietal, occipital and cingulate areas of the cerebral cortex, CA1 and CA3 layer of the hippocampus) to a decrease preceded by a transient increase (frontal area of the cerebral cortex, caudate nucleus). The extent of these changes depends on the duration of exposure to hyperphenylalaninaemia as well as on the degree of brain maturation, but can even be observed in the brain of the adult mouse on a hyperphenylalaninaemic regimen for 11 days. Since the hippocampus has been shown to be involved in the long-term storage of information, damage to this structure by hyperphenylalaninaemia may provide a clue to the global mental retardation observed in untreated PKU.
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PMID:The effect of hyperphenylalaninaemia on the muscarinic acetylcholine receptor in the HPH-5 mouse brain. 812 72

The amino acid proline has long been suspected to serve as a modulator of synaptic transmission in the mammalian brain, but no such function has been identified. The selective expression of high affinity proline transport by a subset of glutamate pathways suggested that proline might play a role in synaptic transmission at these sites. This idea was tested with use of one such pathway, the Schaffer collateral-commissural projection to CA1 pyramidal cells of the rat hippocampus. Proline enhanced the initial slope of the field EPSP without affecting axonal excitability or the magnitude of paired-pulse facilitation. Proline-induced potentiation far outlasted the period of proline application and required the activation of NMDA receptors. Proline enhanced Schaffer collateral-commissural synaptic transmission even when the connections between areas CA1 and CA3 had been interrupted. Potentiation was observed with a proline concentration normally present in human CSF (3 microM). A concentration typical of CSF in persons with the genetic disorder hyperprolinemia type II (30 microM) produced a somewhat greater effect. Occlusion experiments suggested that proline-induced potentiation and tetanus-induced long-term potentiation utilize largely distinct transduction mechanisms. Proline-induced potentiation could be blocked by a prior high frequency stimulus, whether or not the stimulus evoked long-term potentiation. These results suggest that endogenous extracellular proline regulates the basal function of some glutamate synapses by maintaining them in a partially potentiated state. They may also facilitate understanding of the seizures and/or mental retardation associated with genetic disorders of proline metabolism.
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PMID:Proline-induced potentiation of glutamate transmission. 925 26

We investigated the phenomenon of long-term potentiation (LTP) in a genetic model of Down Syndrome, the segmental trisomy mouse (Ts65Dn). Ts65Dn mice survive to adulthood and have an extra chromosome that contains a segment of chromosome 16 homologous to human chromosome 21. In this study, field excitatory postsynaptic potentials (fEPSP) were recorded from the CA1 area of in vitro hippocampal slices from diploid and Ts65Dn mice, and LTP was induced by a single tetanizing pulse train (1 sec in duration) at 100 Hz. The hippocampus from both young (2 months) and older (9 months) Ts65Dn mice had a reduced LTP over a period of 60 min compared with LTP in age-matched controls. This finding may explain the reported behavioral and learning impairments in Ts65Dn mice; it suggests that this mouse model can be used to study the role of altered synaptic plasticity in mental retardation of Down Syndrome.
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PMID:Altered long-term potentiation in the young and old Ts65Dn mouse, a model for Down Syndrome. 951 25

Fetal alcohol syndrome is a major cause of mental retardation. We investigated possible long-lasting effects of alcohol on the hippocampus using a model for human third trimester brain development. Treatment of neonatal rats with an ethanol vapor atmosphere of 39.4+/-2.6 mg ethanol/liter of air for 3 h a day from postnatal day 4 through 9 produced daily blood ethanol levels of 351+/-14 mg/dL. Separation control animals were removed from their mothers in parallel with the ethanol vapor treatment, while suckle controls were left to develop normally. We prepared hippocampal slices from these animals between postnatal days 45 and 60 and recorded extracellular responses to Schaffer collateral stimulation. The maximum population spike in the CA1 pyramidal region and population excitatory postsynaptic potentials in the stratum radiatum did not differ significantly between groups. However, slices prepared from ethanol-treated rats as opposed to separation and suckle controls required larger stimulus currents to produce normal postsynaptic responses. In addition, the ratio of the population excitatory postsynaptic potential (pEPSP) slope to the presynaptic volley was significantly reduced in ethanol-treated rats. Ethanol vapor-treated rats and separation control rats did not exhibit any significant changes in long-term potentiation or paired-pulse potentiation compared with normal suckle controls. These results suggest that early postnatal ethanol treatment produces a long-lasting reduction in synaptic efficacy but not plasticity.
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PMID:Ethanol exposure during the third trimester equivalent results in long-lasting decreased synaptic efficacy but not plasticity in the CA1 region of the rat hippocampus. 1002 83

Entorhinal cortex (EC), fascia dentata (FD), hippocampus (HP), and basal ganglia (BG) were studied in Rett syndrome (RS) cases and compared with control brains and an autism case. Kluver-Barrera and Golgi methods were used. In RS most of the areas of EC, HP, and FD showed severe cell hypochromia. In the EC all cells of layer II and most in layer III were in a state of total chromatolysis or were "ghost" cells, but the cells of layers V and VI were preserved and moderately hyperchromic. In FD and HP the majority of the granular cells and cells of CA3 and CA4 fields were severely hypochromic, whereas in the CA1 field most cells were normal or slightly hypercaryochromic. In BG mostly mild or moderate aberration from normal cell structure was observed: in striatum, mild hypercaryochromia of small neurons and more expressive hyperchromia of large neurons were found; and in pallidum, mild or moderate hypercaryochromia to severe hyperchromia in pallidum internum was found. Degeneration of thick myelinated fibers was evident in pallidum. Large striatal and pallidal neurons showed signs of constructive changes in Golgi slices. These data allow the determination of the cause of the main symptoms of RS. The motor disorders, including specific stereotyped movements, could be related to the enhanced activity of BG cells due to their deafferentation from the side of the neocortex and to supposed hyperactivity of the EC-striatal pathway; the mental retardation and epileptic seizures could be due to FD-HP involvement.
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PMID:Morphological study of the entorhinal cortex, hippocampal formation, and basal ganglia in Rett syndrome patients. 1034 23

Rab GDP dissociation inhibitor alpha (Rab GDIalpha) is a regulator of the Rab small G proteins implicated in neurotransmission, and mutations of Rab GDIalpha cause human X-linked mental retardation associated with epileptic seizures. In Rab GDIalpha-deficient mice, synaptic potentials in the CA1 region of the hippocampus displayed larger enhancement during repetitive stimulation, which was apparently opposite to the phenotype of Rab3A-deficient mice. Furthermore, the Rab GDIalpha-deficient mice showed hypersensitivity to bicuculline, an inducer of epileptic seizures. These results suggest that Rab GDIalpha plays a specialized role in Rab3A recycling to suppress hyperexcitability via modulation of presynaptic forms of plasticity.
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PMID:Role of rab GDP dissociation inhibitor alpha in regulating plasticity of hippocampal neurotransmission. 1102 56

Down syndrome (DS, trisomy 21, Ts21) is the most common known cause of mental retardation. In vivo structural brain imaging in young DS adults, and post-mortem studies, indicate a normal brain size after correction for height, and the absence of neuropathology. Functional imaging with positron emission tomography (PET) shows normal brain glucose metabolism, but fewer significant correlations between metabolic rates in different brain regions than in controls, suggesting reduced functional connections between brain circuit elements. Cultured neurons from Ts21 fetuses and from fetuses of an animal model for DS, the trisomy 16 (Ts16) mouse, do not differ from controls with regard to passive electrical membrane properties, including resting potential and membrane resistance. On the other hand, the trisomic neurons demonstrate abnormal active electrical and biochemical properties (duration of action potential and its rates of depolarization and repolarization, altered kinetics of active Na(+), Ca(2+) and K(+) currents, altered membrane densities of Na(+) and Ca(2+) channels). Another animal model, the adult segmental trisomy 16 mouse (Ts65Dn), demonstrates reduced long-term potentiation and increased long-term depression (models for learning and memory related to synaptic plasticity) in the CA1 region of the hippocampus. Evidence suggests that the abnormalities in the trisomy mouse models are related to defective signal transduction pathways involving the phosphoinositide cycle, protein kinase A and protein kinase C. The phenotypes of DS and its mouse models do not involve abnormal gene products due to mutations or deletions, but result from altered expression of genes on human chromosome 21 or mouse chromosome 16, respectively. To the extent that the defects in signal transduction and in active electrical properties, including synaptic plasticity, that are found in the Ts16 and Ts65Dn mouse models, are found in the brain of DS subjects, we postulate that mental retardation in DS results from such abnormalities. Changes in timing and synaptic interaction between neurons during development can lead to less than optimal functioning of neural circuitry and signaling then and in later life.
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PMID:On the cause of mental retardation in Down syndrome: extrapolation from full and segmental trisomy 16 mouse models. 1133 79


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