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)

The mechanisms by which the atypical neuroleptic clozapine produces its therapeutic effects in the treatment of schizophrenia without causing the extrapyramidal side effects that are characteristic of most antipsychotic drugs remain unclear. Recently, a single injection of the typical antipsychotic haloperidol has been shown to increase c-fos expression in the striatum [Dragunow et al. (1990) Neuroscience 37, 287-294]. C-fos is a proto-oncogene that encodes a 55,000 mol. wt phosphoprotein, Fos, which is thought to assist in the regulation of "target genes" containing an AP-1 binding site. Because a wide variety of physiological and pharmacological stimuli increase c-fos expression, it has been proposed that Fos immunohistochemistry might be useful in mapping functional pathways in the central nervous system. The present experiments examined some potential neuroanatomical differences in the actions of clozapine and haloperidol by comparing their effects on c-fos expression in the medial prefrontal cortex, nucleus accumbens, striatum and lateral septum. The effects of the selective dopamine receptor antagonists SCH 23390 (D1) and raclopride (D2) were also examined. Haloperidol (0.5, 1 mg/kg) and raclopride (1, 2 mg/kg) produced large increases in the number of Fos-containing neurons in the striatum and nucleus accumbens. SCH 23390 (0.5, 1 mg/kg) reduced the number of Fos-positive neurons in the nucleus accumbens and striatum, and had no effect in the other regions. Neither haloperidol nor raclopride increased the number of Fos-positive neurons in the medial prefrontal cortex. Haloperidol, but not raclopride, produced a modest increase in c-fos expression in the lateral septal nucleus. Clozapine (10, 20 mg/kg) was without effect in the striatum; however, it significantly increased the number of Fos-positive neurons in the nucleus accumbens, medial prefrontal cortex and lateral septal nucleus. Destruction of mesotelencephalic dopaminergic neurons with 6-hydroxydopamine abolished the increase in Fos expression in the nucleus accumbens and striatum produced by haloperidol and raclopride, and also blocked the clozapine-induced increase in the nucleus accumbens. However, the inductive effects of clozapine and haloperidol on c-fos expression in the lateral septal nucleus and of clozapine in the medial prefrontal cortex were not affected by the 6-hydroxydopamine lesions. These results suggest that clozapine's unique therapeutic profile may be related to its failure to induce Fos in the striatum as well as its idiosyncratic actions in the lateral septum and medial prefrontal cortex. The effects of clozapine in these latter regions do not appear to be mediated by dopaminergic mechanisms.
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PMID:Neuroleptics increase c-fos expression in the forebrain: contrasting effects of haloperidol and clozapine. 134 6

Synapsin II (formerly known as protein III) is a synaptic vesicle-associated neuronal phosphoprotein that may be involved in the regulation of neurotransmitter release. Synapsin II was studied in postmortem brain samples from 132 individuals with various neuropsychiatric and medical diagnoses. Molecular weight variants of synapsin II were present in 73% of samples from alcoholic individuals but in only 31% of samples from non-diseased individuals, thus confirming our two previous reports of an association between synapsin II variants and alcoholism. The presence of synapsin II variants was not correlated with age or nutritional state. Synapsin II variants were also present in 56% of samples from individuals with schizophrenia and 41% of samples from individuals with Huntington's disease. Synapsin II variants were present in samples from children and young adults, consistent with the possibility that synapsin II variants may reflect a genetically inherited trait. Synapsin II variants were not found in any of 18 rodent models of alcoholism, aging, or vitamin B deficiency, suggesting that synapsin II variants may be a uniquely human trait.
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PMID:An analysis of synapsin II, a neuronal phosphoprotein, in postmortem brain tissue from alcoholic and neuropsychiatrically ill adults and medically ill children and young adults. 214 98

The pathophysiology of schizophrenia may involve perturbations of synaptic organization during development. The presence of cytoarchitectural abnormalities that may reflect such perturbations in the brains of patients with this disorder has been well-documented. Yet the mechanistic basis for these features of the disorder is still unknown. We hypothesized that altered regulation of the neuronal growth-associated protein GAP-43, a membrane phosphoprotein found at high levels in the developing brain, may play a role in the alterations in brain structure and function observed in schizophrenia. In the mature human brain, GAP-43 remains enriched primarily in association cortices and in the hippocampus, and it has been suggested that this protein marks circuits involved in the acquisition, processing, and/or storage of new information. Because these processes are known to be altered in schizophrenia, we proposed that GAP-43 levels might be altered in this disorder. Quantitative immunoblots revealed that the expression of GAP-43 is increased preferentially in the visual association and frontal cortices of schizophrenic patients, and that these changes are not present in other neuropsychiatric conditions requiring similar treatments. Examination of the levels of additional markers in the brain revealed that the levels of the synaptic vesicle protein synaptophysin are reduced in the same areas, but that the abundance of the astrocytic marker of neurodegeneration, the glial fibrillary acidic protein, is unchanged. In situ hybridization histochemistry was used to show that the laminar pattern of GAP-43 expression appears unaltered in schizophrenia. We propose that schizophrenia is associated with a perturbed organization of synaptic connections in distinct cortical associative areas of the human brain, and that increased levels of GAP-43 are one manifestation of this dysfunctional organization.
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PMID:Levels of the growth-associated protein GAP-43 are selectively increased in association cortices in schizophrenia. 894 81

The human synapsin III gene (synapsin III) is a member of a neuron-specific phosphoprotein gene family involved in short-term neurotransmitter release. We mapped synapsin III to chromosomal region 22q13 (13.1-13.31) by fluorescence in situ hybridization, a region that has been identified as a potential schizophrenia susceptibility locus. The dinucleotide repeat marker D22S280 located in intron 5 of synapsin III was genotyped in a linkage and family-based association study to assess the role of the synapsin III locus in the etiology of schizophrenia. In 12 pedigrees with periodic catatonia comprising 135 individuals, we found exclusion of linkage of marker D22S280 using lod score analysis with autosomal dominant/recessive models as well as affected only LOD score methods with dominant/recessive models. In a family-based association study of 61 unrelated parent-offspring trios with schizophrenia (according to the the Diagnostic and Statistical Manual of Mental Disorders, fourth edition [DSM-IV, American Psychiatric Association, 1994]), we found no association of individual D22S280 alleles to disease. Results of a multiallelic transmission/disequilibrium test (TDT(max) = 3.00; P = 0.55) challenged the possibility that D22S280 alleles appear with DSM-IV schizophrenia more frequently than expected. In addition, no evidence for gender differences or parent-of-origin effects were found. Thus, the synapsin III locus at chromosome 22q13 is not likely to contain a schizophrenia susceptibility gene.
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PMID:Linkage and family-based association study of schizophrenia and the synapsin III locus that maps to chromosome 22q13. 1089 20

The three Nobel laureates Arvid Carlsson, Paul Greengard and Eric Kandel have made pioneering discoveries concerning slow synaptic transmission between neurons. As common theme, for which the Nobel Prize in Physiology or Medicine for 2000 is given, the Nobel Assembly chose 'signal transduction in the nervous system'. The work of Carlsson led to the discovery of dopamine as transmitter in the brain and opened the way for the development of the levodopa therapy of patients suffering from Parkinson's disease. His later work concentrated on the dopamine hypothesis of schizophrenia and the rationale for the mechanism of action of antipsychotics. Greengard pioneered the field of receptor-mediated phosphorylation and dephosphorylation of brain proteins. He was the first to describe the cyclic-AMP-dependent protein kinase in the brain and the activation of this kinase following dopamine receptor activation. A substrate enriched in cells that bear dopamine receptors is 'dopamine- and cyclic-AMP-regulated phosphoprotein' (DARPP-32). Phosphorylation by the cyclic-AMP-dependent kinase influences its protein phosphatase inhibiting capacity and, as such, DARPP-32 is an important 'feed-forward activator' in the dopamine signal transduction cascade. Kandel received the prize for his contributions to our understanding of the neural substrate of learning and memory. Most of his work was carried out in the sea slug Aplysia in which he was able to relate three psychologically defined forms of learning--habituation, sensitisation, and classical conditioning--to subcellular processes and intercellular signalling. Kandel is known all over the world for his eminent textbook Principles of Neural Science which inspired generations of young neuroscientists. It seems that it is not so much the signal transduction that joins these laureates but their outstanding conceptual approach to, in fact, three different themes of the neurosciences during the second part of the last century.
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PMID:[Nobel prize in physiology of medicine for year 2000 for research of signal transduction in the nervous system]. 1110 53

The p53 tumor-suppressor gene, encoding a phosphoprotein, is a key element in maintaining genomic stability and cell apoptosis. It is also implicated in nervous-system development. In order to examine the role of the p53 gene for the pathogenesis of schizophrenic disorders, patients (n=155) and control subjects (n=168) were genotyped for the p53-Pro72Arg polymorphism. The results demonstrated no association with schizophrenia and/or age of onset for this polymorphism.
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PMID:Association study of the p53-gene Pro72Arg polymorphism in schizophrenia. 1181 47

Dopaminergic and glutamatergic neurotransmissions in the striatum play an essential role in motor- and reward-related behaviors. Dysfunction of these neurotransmitter systems has been found in Parkinson's disease, schizophrenia, and drug addiction. Cyclin-dependent kinase 5 (CDK5) negatively regulates postsynaptic signaling of dopamine in the striatum. This kinase also reduces the behavioral effects of cocaine. Here we demonstrate that, in addition to a postsynaptic role, CDK5 negatively regulates dopamine release in the striatum. Inhibitors of CDK5 increase evoked dopamine release in a way that is additive to that of cocaine. This presynaptic action of CDK5 also regulates glutamatergic transmission. Indeed, inhibition of CDK5 increases the activity and phosphorylation of N-methyl-d-aspartate receptors, and these effects are reduced by a dopamine D1 receptor antagonist. Using mice with a point mutation of the CDK5 site of the postsynaptic protein DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, molecular mass of 32 kDa), in the absence or in the presence of a dopamine D1 receptor antagonist, we provide evidence that CDK5 inhibitors potentiate dopaminergic transmission at both presynaptic and postsynaptic locations. These findings, together with the known ability of CDK5 inhibitors to prevent degeneration of dopaminergic neurons, suggest that this class of compounds could potentially be used as a novel treatment for disorders associated with dopamine deficiency, such as Parkinson's disease.
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PMID:Cyclin-dependent kinase 5 regulates dopaminergic and glutamatergic transmission in the striatum. 1476 20

How genes and environment interface to generate major psychiatric disorders such as schizophrenia has been puzzling, as are the relative roles of neurons and glia in such disturbances. Tomonaga and colleagues have recently reported striking neurobehavioral abnormalities in mice expressing Borna disease virus phosphoprotein (BDV-P) selectively in glial cells. The study provides a novel approach of linking environmental and genetic factors to behavior by producing genetically engineered mice. The key role for glial BDV-P implicates neuron-glia interactions in the pathogenesis of psychiatric conditions.
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PMID:Neuron-glia interactions clarify genetic-environmental links in mental illness. 1516 31

Schizophrenia is a debilitating mental disorder. The TP53 tumor suppressor gene, encoding a phosphoprotein, is a key element in maintaining genomic stability and cell apoptosis. Recently, reduced risk of cancer in patients of schizophrenia has been reported. Some evidence also suggests the possible implication of TP53 in neurodevelopment. In order to examine the role of the TP53 gene in the pathogenesis of schizophrenic disorders, we investigated the genetic association between a functional polymorphism rs1042522 and schizophrenia by sequencing the fragment covering 72Pro> Arg in 701 cases and 695 controls in this work. In addition, we studied two other SNPs rs2078486 and rs8064946 by allele-specific PCR in the same samples. Though rs1042522 and rs8064946 did not show positive association with schizophrenia, we did observe statistically significant differences on SNP rs2078486 (P-value = 0.029; OR = 1.21; 95% CI 1.02-1.42) and on haplotype CAC (P-value = 0.0068; OR = 1.36; 95% CI 1.09-1.70). These results demonstrated that TP53 might play a role in susceptibility to schizophrenia.
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PMID:Tumor suppressor gene TP53 is genetically associated with schizophrenia in the Chinese population. 1545 Jun 81

We previously demonstrated that chronic treatment with the dopamine-D2 receptor antagonist, haloperidol, increases mRNA and protein content of the phosphoprotein, synapsin II, in the rat striatum. Since dopamine-D2 receptor antagonism and dopamine-D1 receptor blockade can have opposing effects on gene expression, the present investigation compared the effects of haloperidol with those of the dopamine-D1 receptor antagonist, R-[+]-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390), on the expression of synapsin II protein. Haloperidol and SCH23390 respectively elevated and reduced concentrations of the molecule in mouse primary midbrain cell cultures. Additional experiments revealed that the dopamine-D1 receptor agonist, R-[+]-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzapezine-7,8-diol (SKF38393), upregulated the phosphoprotein in these cells. Furthermore, in vivo rat studies demonstrated that chronic haloperidol treatment increases synapsin II protein expression in the medial prefrontal cortex and nucleus accumbens, as was observed in the striatum. In contrast, chronic SCH23390 administration reduced concentrations of this protein in all of these regions, although the reductions seen in the medial prefrontal cortex were insignificant. Neither haloperidol nor the dopamine-D1 receptor antagonist affected synapsin I protein expression in any of the studied brain areas. Based on these findings, we propose dopamine receptors may specifically regulate synapsin II expression through a cyclic AMP-dependent pathway. Since synapsin II is involved in neurotransmitter release and synaptogenesis, and changes in synaptic efficacy and structure are suggested in schizophrenia as well as in haloperidol treatment, our findings offer insight into the mechanistic actions of the antipsychotic agent at the synaptic level.
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PMID:Dopamine-D1 and -D2 receptors differentially regulate synapsin II expression in the rat brain. 1641 26


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