Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several lines of evidence suggest a possible role for reelin in the pathogenesis of neurodevelopmental diseases, particularly schizophrenia. Genes encoding reelin and proteins involved in the signal pathway of reelin are thus candidate genes for schizophrenia. We examined the polymorphic CGG repeat in the 5'-untranslated region (UTR) of the reelin gene, which was recently found to be associated with autistic disorder, and the CGG repeat in the 5' UTR region of the very low density protein receptor (VLDLR) gene, which was reported to be associated with sporadic Alzheimer's disease, for allelic association with schizophrenia. The subjects consisted of 150 patients and 150 controls matched for sex, age and ethnicity (Japanese). We found no significant association of schizophrenia with the trinucleotide repeat polymorphism of the reelin or VLDLR genes, suggesting that these polymorphisms do not have a major role in the pathogenesis of the disease.
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PMID:Association analysis of polymorphic CGG repeat in 5' UTR of the reelin and VLDLR genes with schizophrenia. 1236 88

Reelin and glutamic acid decarboxylase (GAD)67 expressed by cortical gamma-aminobutyric acid-ergic interneurons are down-regulated in schizophrenia. Because epidemiological studies of schizophrenia fail to support candidate gene haploinsufficiency of Mendelian origin, we hypothesize that epigenetic mechanisms (i.e., cytosine hypermethylation of CpG islands present in the promoter of these genes) may be responsible for this down-regulation. Protracted l-methionine (6.6 mmolkg for 15 days, twice a day) treatment in mice elicited in brain an increase of S-adenosyl-homocysteine, the processing product of the methyl donor S-adenosyl-methionine, and a marked decrease of reelin and GAD67 mRNAs in both WT and heterozygous reeler mice. This effect of l-methionine was associated with an increase in the number of methylated cytosines in the CpG island of the reelin promoter region. This effect was not observed for GAD65 or neuronal-specific enolase and was not replicated by glycine doses 2-fold greater than those of l-methionine. Prepulse inhibition of startle declined at a faster rate as the prepulsestartle interval increased in mice receiving l-methionine. Valproic acid (2 mmolkg for 15 days, twice a day) reverted l-methionine-induced down-regulation of reelin and GAD67 in both WT and heterozygous reeler mice, suggesting an epigenetic action through the inhibition of histone deacetylases. The same dose of valproate increased acetylation of histone H3 in mouse brain nearly 4-fold. This epigenetic mouse model may be useful in evaluating drug efficacy on schizophrenia vulnerability. Hence the inhibition of histone deacetylases could represent a pharmacological intervention mitigating epigenetically induced vulnerability to schizophrenia in individuals at risk.
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PMID:An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability. 1248 Oct 28

The neuropathological features of schizophrenia are suggestive of a developmentally induced impairment of synaptic connectivity. Semaphorin 3A (sema3A) might contribute to this process because it is a secreted chemorepellant which regulates axonal guidance. We have investigated sema3A in the cerebellum (an area in which expression persists in adulthood), and measured its abundance in 16 patients with schizophrenia and 16 controls. In adults, sema3A was predominantly localized to the inner part of the molecular layer neuropil, whereas infants and rats showed greater labelling of Purkinje cell bodies. Sema3A was increased in schizophrenia, as shown by enzyme-linked immunosorbent assay (+28%; P<0.05) and immunohistochemistry (+45%; P<0.01). We also measured reelin mRNA, since reelin is involved in related developmental processes and is decreased in other brain regions in schizophrenia. Reelin mRNA showed a trend reduction in the subjects with schizophrenia (-26%; P=0.07) and, notably, was negatively correlated with sema3A. Sema3A also correlated negatively with synaptophysin and complexin II mRNAs. The results show that sema3A is elevated in schizophrenia, and is associated with downregulation of genes involved in synaptic formation and maintenance. In this respect, sema3A appears to contribute to the synaptic pathology of schizophrenia, perhaps via ongoing effects of persistent sema3A elevation on synaptic plasticity. The findings are consistent with an early neurodevelopmental origin for the disorder, and the reciprocal changes in sema3A and reelin may be indicative of a pathogenic mechanism that affects the balance between trophic and inhibitory factors regulating synaptogenesis.
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PMID:The axonal chemorepellant semaphorin 3A is increased in the cerebellum in schizophrenia and may contribute to its synaptic pathology. 1261 Jun 47

Two main pieces of neurobiological evidence are adduced to support an early neurodevelopmental component to schizophrenia. Firstly, an abnormal distribution of neurons, especially interstitial white matter neurons (IWMNs). Secondly, decreased expression of reelin, a key developmental signalling molecule. Although influential, neither result is wholly established, and a possible link between them has not been examined. We addressed both issues, in superior temporal cortex, in 12 subjects with schizophrenia and 14 controls. The distribution and density of IWMNs, immunostained with the neuronal marker NeuN, was increased in the superficial white matter in schizophrenia (+16%; P=0.03). IWMN density in deep white matter was unaffected. Using in situ hybridization, reelin mRNA was found to be expressed by many IWMNs, layer I neurons, and scattered interneurons. Superficial IWMNs (P=0.008) and layer I neurons (P=0.036) both expressed less reelin mRNA per cell in schizophrenia, with a trend for deep IWMNs (P=0.055). In conclusion, we replicated findings of increased IWMN density, and of decreased reelin expression, in schizophrenia. The loss of reelin reflects, at least partly, its decreased expression by IWMNs. These findings together support neurodevelopmental theories of the disorder, and indicate a link between reelin and IWMNs in this process, consistent with evidence from the heterozygous reeler mutant mouse. The alterations may contribute to the aberrant synaptic connectivity seen in schizophrenia. However, the functional implications of the abnormalities, as well as the mechanisms involved, remain to be fully elucidated.
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PMID:Interstitial white matter neurons express less reelin and are abnormally distributed in schizophrenia: towards an integration of molecular and morphologic aspects of the neurodevelopmental hypothesis. 1293 Dec 9

In brains of patients with schizophrenic and affective disorders pathomorphological changes have been shown focussing in frontal and temporal cortex. The volume reduction in prefrontal cortex of schizophrenic patients is hypothesized to be based on a reduction of neuropil. A decrease of synaptic proteins and a decrease of dendritic spines of pyramidal cells can additionally be the origin of disconnections of neurons. Affection of the glutamatergic, GABA-ergic and dopaminergic system and reduction of interneurons could be the correlate of a deficient neuronal network which might be combined with exogen factors generate psychotic symptoms. Reelin and associated proteins are candidate molecules. Their dysregulation might explain essential features of the dysfunctional network of schizophrenia.
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PMID:[The importance of interneurons in schizophrenic and affective disorders]. 1294 40

Because heterozygous reeler (HR) mice share some abnormal traits with schizophrenic patients, and schizophrenia is often accompanied by impairment of olfactory function, this study examines reelin in the olfactory bulb of the HR mouse. In the WT mouse, reelin immunoreactivity is found in the extracellular matrix, and in the cytoplasm of olfactory nerve fibers, GABAergic interneurons, and glutamatergic mitral cells. Western blot analysis reveals that reelin immunoreactivity in the HR mouse is reduced by 45% compared to WT mouse. This is especially evident in the glomerular GABAergic interneurons. In WT mitral cells, reelin is found in discrete clumps near the axon hillock and within the axon. In the HR mouse, reelin axonal staining is diffuse and densely packed. In the rostral migratory stream of the HR mouse, immunolabeling shows an accumulation of reelin-containing neuronal precursors, apparently unable to shift from tangential to radial migration. These observations indicate that there is a downregulation of reelin in the HR mouse and suggest that secretion of reelin may be compromised. Further studies of the HR mouse may provide a new basis for understanding the role of reelin in the adult CNS, especially as it may relate to schizophrenia.
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PMID:Immunocytochemical localization of reelin in the olfactory bulb of the heterozygous reeler mouse: an animal model for schizophrenia. 1466 25

A down-regulation of reelin and glutamic acid decarboxylase (GAD) 67 mRNAs was detected in gamma-aminobutyric acid (GABA)ergic cortical interneurons of schizophrenia (SZ) postmortem brains (10), suggesting that the availability of GABA and reelin may be decreased in SZ cortex. In situ hybridization of the mRNA encoding for DNA-methyltransferase 1, which catalyzes the methylation of promoter CpG islands, shows that the expression of this mRNA is increased in cortical GABAergic interneurons but not in pyramidal neurons of SZ brains. Counts of reelin mRNA-positive neurons in Brodmann's area 10 of either nonpsychiatric subjects or SZ patients show that the expression of reelin mRNA is decreased in layer-I, -II, and -IV GABAergic interneurons of SZ patients. These findings are consistent with the hypothesis that the increase of DNA-methyltransferase 1 expression in telencephalic GABAergic interneurons of SZ patients causes a promoter hypermethylation of reelin and GAD(67) and perhaps of other genes expressed in these interneurons. It is difficult to decide whether this dysfunction of GABAergic neurons detected in SZ is responsible for this disease or is a consequence of this disorder. Although at present we cannot differentiate between these two alternatives, it is important to consider that so far a molecular pathology of cortical GABAergic neurons appears to be the most consistent finding associated with SZ morbidity.
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PMID:DNA-methyltransferase 1 mRNA is selectively overexpressed in telencephalic GABAergic interneurons of schizophrenia brains. 1468 36

Between 1997 and 2002, 48 data sets from the hippocampus were produced on samples from the Stanley Neuropathology Consortium. From these data sets, 224 total measures were available from the various subdivisions of the hippocampus. An integrative analysis of these measures was performed using a multivariate, nonparametric analysis of variance (ANOVA). ANOVA with correction for multiple comparisons indicated that parvalbumin-containing cells in CA2 were reduced in schizophrenia and bipolar disorder. In addition, reelin protein in the molecular layer of the dentate gyrus was decreased in schizophrenia, bipolar disorder, and depression at the trend level of statistical significance (P=0.065). These results strongly suggest a dysfunction of inhibitory GABA-ergic interneurons in severe mental illness. Without correction for multiple comparisons, 31 measures were abnormal in at least one disease, whereas 11 measures would be expected to appear abnormal by chance. Abnormal molecules included measures of synaptic density or neuronal plasticity (reelin, SNAP-25, BDNF, Complexin I and II), as well as parvalbumin, tyrosine receptor kinase A, glucocorticoid receptors, glutamate NR1 receptor subunits, serotonin 5HT2(A) and 5HT1(B) receptors, and dopamine D(5) receptors.
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PMID:Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium. 1470 30

Inhibitory GABAergic interneurons of prefrontal cortex (PFC) appear to play an important role in the regulation of intermittent pyramidal neuron columnary firing and in the neuronal plasticity that mediate cognitive functions. In schizophrenia (SZ), cognitive defects and dysfunctions in pyramidal neuronal columnary firing appear to depend on abnormalities of GABAergic neurons. These abnormalities include a decrease of GAD67 and reelin expression, which result in a reduction of cortical inhibitory input to spine postsynaptic densities as a result of the decrease of GABA concentration at the synaptic cleft, and of neurotrophic stimuli as a result of the decrease of reelin secreted into the extracellular matrix. Our studies show that alterations in chromatin remodeling related to a selective upregulation of DNA-5-cytosine methyltransferase (DNMT) expression in GABAergic neurons of SZ PFC may induce a hypermethylation of reelin and GAD67 promoter CpG islands, which downregulates their expression. In addition, we report preliminary evidence suggesting that by targeting this chromatin-remodeling deficit with inhibitors of histone deacetylases (HDAC), it may be possible to reduce the DNMT upregulation via a covalent modification of nucleosomal histone tails, underscoring the possibility that by addressing a chromatin remodeling deficit, one may treat psychiatric disorders.
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PMID:GABAergic cortical neuron chromatin as a putative target to treat schizophrenia vulnerability. 1497 67

The downregulation of the Reelin gene (RELN) that occurs in schizophrenic brains, which are characterized by pyramidal neurons with shortened dendrites and by reduced expression densities of dendritic spines, may well result from hypermethylation of the RELN promoter. In the adult mammalian brain, gamma-aminoburytic acid-secreting (GABAergic) interneurons release RELN into the extracellular matrix, where it binds with high affinity to the integrin receptors present at dendritic spine postsynaptic densities and likely plays a role, elaborated in this article, in synaptic plasticity. In heterozygous reeler mice, which are haploinsufficient in RELN, inhibitors of histone deacetylase increase DNA demethylase activity and restore RELN expression. Such inhibitors could thus be of therapeutic value in mitigating vulnerability to schizophrenia among high-risk individuals.
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PMID:REELIN and schizophrenia: a disease at the interface of the genome and the epigenome. 1499 61


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