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)

Dopamine has been implicated in the pathophysiology of schizophrenia, and the entorhinal cortex (ERC) is thought to be a site of structural pathology in this disorder. However, relatively little is known about the dopaminergic (DA) innervation of ERC in the primate brain. In this study, immunohistochemical methods and antibodies directed against tyrosine hydroxylase (TH) and dopamine were used to determine the organization of DA axons in the ERC of macaque monkeys. The anti-TH antibody used in this study appeared predominantly to identify DA axons, as demonstrated by its failure to label fibers that were immunoreactive with an antibody against dopamine-beta-hydroxylase in double-labeling experiments. In addition, the regional and laminar distributions of TH-immunoreactive fibers were strikingly similar to those labeled with the anti-dopamine antibody. With both antibodies, cytoarchitectonically identified subdivisions of monkey ERC (Amaral et al., 1987) differed in both the density and laminar distribution of labeled fibers. Immunoreactive processes exhibited a substantial rostral-to-caudal gradient of decreasing density across subdivisions of ERC, and the density of labeled fibers also decreased from medial to lateral in the rostral but not in the caudal subdivisions of ERC. The laminar distribution of labeled fibers differed both between and within subdivisions. For example, in the olfactory and rostral subdivisions of ERC, the superficial layers contained a very high density of immunoreactive processes, whereas in the intermediate region, three bands of labeled fibers were seen in layers I, III-IV, and VI. In addition, radial columns of fibers interdigitated with areas of decreased density were present between layers I and III. Although the overall density of labeled fibers was greater in lateral than in the caudal subdivisions of ERC, these regions had similar laminar distribution patterns. In these areas of monkey ERC, labeled processes were highest in density in deep layer I, and homogeneously distributed in the other cortical layers. These findings demonstrate that the DA innervation of monkey ERC is complex, and follows laminar- and subdivision-specific patterns. These patterns of distribution suggest the possible interactions that DA axons may have with other elements of ERC circuitry, and may provide insight into the possible functional roles of dopamine in ERC in both normal and disease states.
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PMID:The dopaminergic innervation of monkey entorhinal cortex. 790 2

Studies of the trophic activities of brain-derived neurotrophic factor and neurotrophin-3 indicate that both molecules support the survival of a number of different embryonic cell types in culture. We have shown that mRNAs for brain-derived neurotrophic factor and neurotrophin-3 are localized to specific ventral mesencephalic regions containing dopaminergic cell bodies, including the substantia nigra and ventral tegmental area. In the present study, in situ hybridization with 35S-labeled cRNA probes for the neurotrophin mRNAs was combined with neurotoxin lesions or with immunocytochemistry for the catecholamine-synthesizing enzyme tyrosine hydroxylase to determine whether the dopaminergic neurons, themselves, synthesize the neurotrophins in adult rat midbrain. Following unilateral destruction of the midbrain dopamine cells with 6-hydroxydopamine, a substantial, but incomplete, depletion of brain-derived neurotrophic factor and neurotrophin-3 mRNA-containing cells was observed in the ipsilateral substantia nigra pars compacta and ventral tegmental area. In other rats, combined in situ hybridization and tyrosine hydroxylase immunocytochemistry demonstrated that the vast majority of the neurotrophin mRNA-containing neurons in the substantia nigra and ventral tegmental area were tyrosine hydroxylase immunoreactive. Of the total population of tyrosine hydroxylase-positive cells, double-labeled neurons constituted 25-50% in the ventral tegmental area and 10-30% in the substantia nigra pars compacta, with the proportion being greater in medial pars compacta. In addition, tyrosine hydroxylase/neurotrophin mRNA coexistence was observed in neurons in other mesencephalic regions including the retrorubral field, interfascicular nucleus, rostral and central linear nuclei, dorsal raphe nucleus, and supramammillary region. The present results demonstrate brain-derived neurotrophic factor and neurotrophin-3 expression by adult midbrain dopamine neurons and support the suggestion that these neurotrophins influence dopamine neurons via autocrine or paracrine mechanisms. These data raise the additional possibility that inappropriate expression of the neurotrophins by dopaminergic neurons could contribute to the neuropathology of disease states such as Parkinson's disease and schizophrenia.
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PMID:Dopaminergic neurons in rat ventral midbrain express brain-derived neurotrophic factor and neurotrophin-3 mRNAs. 791 99

The entorhinal cortex plays an important role in learning and memory, and it has been implicated as a site of dysfunction in some neuropsychiatric disorders such as schizophrenia. The organization of many components of the neural circuitry of this region, including dopaminergic afferents, has not been studied in detail. Using immunohistochemical techniques, we examined the density and laminar distribution of axons immunoreactive for tyrosine hydroxylase, the rate limiting enzyme in catecholamine biosynthesis, in the entorhinal cortex of eight control human brains. The density of tyrosine hydroxylase-containing axons decreased from rostral to caudal regions of entorhinal cortex. In addition, there was a prominent medial to lateral gradient of increasing fiber density. This gradient extended into the adjacent transentorhinal cortex, which contained the highest density of labeled axons of the regions studied. The laminar distribution of tyrosine hydroxylase-containing fibers also differed among the subdivisions of the entorhinal cortex. A bilaminar pattern of labeled axons in layers deep I-superficial II and in deep layer VI was present in the intermediate and caudal subdivisions of entorhinal cortex. In contrast, the olfactory and rostral subdivisions, as well as portions of the transentorhinal region, contained a trilaminar pattern, with a high density of tyrosine hydroxylase-immunoreactive axons in layers deep I-superficial II, deep III-IV and deep VI. In addition, radially-oriented bands of labeled fibers were observed extending between deep layer I and layer III, particularly in the rostral subdivision of the entorhinal cortex. In summary, tyrosine hydroxylase-containing afferents to the human entorhinal cortex are distributed in a characteristic regional and laminar pattern, and the lateral regions of the entorhinal cortex and the adjacent transentorhinal cortex are particularly densely innervated. These data contribute to the understanding of the normal circuitry of the human entorhinal cortex, and are of potential relevance to the pathophysiology of certain neuropsychiatric disorders, such as schizophrenia.
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PMID:The distribution of tyrosine hydroxylase-immunoreactive fibers in the human entorhinal cortex. 793 8

The dopamine D4 receptor gene and the closely placed tyrosine hydroxylase (TH) receptor gene are important candidate genes for schizophrenia; both are located on the short arm of chromosome 11. Multipoint linkage analyses excluded linkage of schizophrenia/schizoaffective disorder to both candidate genes in a sample of 15 multiplex and systematically recruited families. This result was not dependent on the definition of the affection status and on the specification of the mode of transmission (insofar as it is monogenic) of the disease. There was no evidence for a subgroup of families being linked. This result does not preclude the possibility that the D4 receptor gene or the TH gene has only a nonmajor effect on the genetic etiology of schizophrenia or that families in other populations are linked.
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PMID:Absence of linkage between schizophrenia and the dopamine D4 receptor gene. 799 33

The discovery of a functional polymorphism within the dopamine D4 receptor gene (DRD4) has not only strengthened the hypotheses implicating DRD4 in the etiology of neuropyschiatric disorders, but also provided a genetic marker for testing these hypotheses. The possibility of the dopamine D4 receptor as a candidate gene for schizophrenia was investigated in a large Swedish kindred segregating for schizophrenia. Linkage to schizophrenia was tested by linkage analyses of 6 polymorphic markers (at 4 loci) in chromosome 11p15.5 including the dopamine D4 receptor (DRD4) and the tyrosine hydroxylase (TH) loci. Schizophrenia was excluded from close linkage to the DRD4 locus using two of the polymorphisms located within the dopamine D4 receptor gene. The first DRD4 polymorphism consists of variation in the number of a 48 bp imperfect direct repeat in the third exon; the second consists of a variable number of repeated G nucleotides in the first intron. In addition, some of the individuals homozygous for four or seven copies of 48 bp repeat alleles were tested for previously reported sequence variation among repeats. No single haplotype of the DRD4 alleles or haplotype of other markers in chromosome 11p15.5 was found to be common to the schizophrenic individuals in this family. Therefore, we find no evidence for linkage of the D4 receptor, or this region of 11p15.5, with genetic susceptibility to schizophrenia in this kindred.
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PMID:Alleles at the dopamine D4 receptor locus do not contribute to the genetic susceptibility to schizophrenia in a large Swedish kindred. 813 5

Our purpose was to test the dopamine D2 receptor gene (DRD2), the tyrosine hydroxylase (TH) gene and the monoamino oxydase A (MAO-A) gene for linkage to schizophrenia and bipolar disorders. We have analyzed seven Italian families with schizophrenia and four families with bipolar disorders for a total of 68 individuals; 32 individuals were affected. Diagnoses were made using the structured clinical interview Schedule for Affective Disorders and Schizophrenia, Lifetime version (SADS-L). The results of our study provide no evidence of linkage between alleles at D2 dopamine receptor loci and schizophrenia or bipolar disorders. The markers TH gene and MAO-A gene give slightly positive or negative results suggesting the utility of further analysis on more informative families.
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PMID:No evidence of linkage between schizophrenia and D2 dopamine receptor gene locus in Italian pedigrees. 871 Jan 85

In addition to their ability to change the electrical properties of neurons, evidence suggests that neurotransmitters are able to alter the cell's metabolism. Transmitter phenotype is labile and expression might be regulated, during development, by the cellular environment of neurons. The study of a key enzyme in the synthesis of catecholamines, tyrosine hydroxylase (TH), has provided clues about these adaptive responses. This enzyme has a large molecular diversity, resulting from the differential splicing of its mRNA, which is tissue-specific and might result in long-term changes in activity of the enzyme and, therefore, in the availability of neurotransmitter at various synapses. The presence of different DNA sequences at the TH locus confers susceptibility to various disorders of the brain, including manic-depressive illness and schizophrenia. Indeed, an association between a rare variant allele of the gene encoding TH and the occurrence of schizophrenia has been found in several populations. New techniques being developed to treat diseases such as Parkinson's disease involve various gene therapies, including a method of transferring genes directly into nerve cells using an adenovirus-based system.
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PMID:The TiPS/TINS Lecture. Catecholamines: from gene regulation to neuropsychiatric disorders. 872 6

Dopamine receptor dysfunction and altered tyrosine hydroxylase activity have both been implicated in the pathophysiology of schizophrenia. Schizophrenic patients and control subjects were examined for allele frequencies in the tyrosine hydroxylase and dopamine D2 and D4 receptor genes. No significant differences of allele or genotype frequencies were found between the two groups after adjustment for multiple comparisons. Neither were any significant relationships observed between allele frequencies and a number of clinical variables within the schizophrenic subsample. When no adjustment was made for multiple testing a few significant tendencies were obtained which warrant further research in extended patient and control materials. The results are compatible with the view that the tyrosine hydroxylase, dopamine receptor D2 and D4 gene polymorphisms examined are not of major importance in the aetiology or pathophysiology of schizophrenia.
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PMID:A search for association between schizophrenia and dopamine-related alleles. 890 11

In addition to their ability to change the electrical properties of neurones, evidence suggests that neurotransmitters are able to alter the cell's metabolism. Transmitter phenotype is labile and expression might be regulated, during development, by the cellular environment of neurones. The study of a key enzyme in the synthesis of catecholamines, tyrosine hydroxylase (TH), has provided clues about these adaptive responses. This enzyme has a large molecular diversity, resulting from the differential splicing of its mRNA, which is tissue-specific and might result in long-term changes in activity of the enzyme and, therefore, in the availability of neurotransmitter at various synapses. The presence of different DNA sequences at the TH locus confers susceptibility to various disorders of the brain, including manic-depressive illness and schizophrenia. Indeed, an association between a rare variant allele of the gene encoding TH and the occurrence of schizophrenia has been found in several populations. New techniques being developed to treat diseases such as Parkinson's disease involve various gene therapies, including a method of transferring genes directly into nerve cells using an adenovirus-based system.
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PMID:The TiPS/TINS lecture. Catecholamines: from gene regulation to neuropsychiatric disorders. 898 38

A series of recent postmortem investigations of the anterior cingulate cortex in schizophrenic brain have suggested that there may be a loss and/or impairment of inhibitory interneurons in layer II. It has been postulated that changes of this type could secondarily result in a relative increase of dopaminergic inputs to GABAergic interneurons. To test this hypothesis, an immunoperoxidase technique was developed to extensively and reliably visualize tyrosine hydroxylase-immunoreactive (TH-IR) varicose fibers in human postmortem cortex. This method has been applied to the anterior cingulate (ACCx; Brodmann area 24) and prefrontal (PFCx: Brodmann area 10) cortices from a cohort of 15 normal control and 10 schizophrenic cases. The number of TH-IR varicosities in contact with large neurons (LN), small neurons (SN), and neuropil (NPL) was blindly analyzed using a computer-assisted microscopic technique. There was no significant difference in density of TH-IR varicosities in apposition with either LN or SN cell bodies observed in either ACCx or PFCx of schizophrenics when compared to normal controls. The density of varicosities was significantly reduced in NPL of layers V and VI in ACCx, but 2 neuroleptic-free cases did not show this change, suggesting that these decreases of TH-IR varicosities may be related to antipsychotic effects on corticostriatal projection cells in this region. When the density of TH-IR varicosities on SNs was compared to that observed on LNs, both groups showed a higher density on SNs. In ACCx, this pattern was much more pronounced for the schizophrenic group, particularly in layer II where the density on SNs was three times higher than that for LNs (P = 0.01). Unlike the changes in layer V, this latter change in layer II showed no relationship to neuroleptic exposure. There was a positive correlation between age and the density of TH-IR varicosities on SNs of layer II in ACCx; however, the patients were younger than the controls and would have been expected to show a lower density, rather than a higher one, if age considerations had accounted for the group differences. Overall, the results reported here suggest that there are no gross differences in the distribution of TH-IR varicosities in various laminae of the dorsolateral prefrontal cortex. In the anterior cingulate region, however, there may be a significant shift in the distribution of TH-IR varicosities from large neurons to small neurons that occurs selectively in layer II of schizophrenic subjects. Using size criteria, the majority of small neurons are likely nonpyramidal, while the majority of large neurons are predominantly pyramidal in nature. Taken together with other accumulating evidence of preferential abnormalities in this lamina of the cingulate region, the findings reported here are consistent with a model of schizophrenia in which a subtle "miswiring" of ventral tegmental inputs may result in a relative, though not absolute, hyperdopaminergic state with respect to an impaired population of GABAergic interneurons.
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PMID:Differential distribution of tyrosine hydroxylase fibers on small and large neurons in layer II of anterior cingulate cortex of schizophrenic brain. 898 51


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