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

Neuregulin-1 (NRG-1) plays important roles in the development and plasticity of the brain, and it has recently been identified as a susceptibility gene for schizophrenia. Though there are rodent data, little is known about its distribution in the human brain. The aim of this study was to ascertain the localization of NRG-1 and its mRNA in multiple regions of the normal adult human brain. We investigated NRG-1 mRNA in 11 subjects using in situ hybridization and northern analysis, and NRG-1 protein in six subjects using immunohistochemistry and Western blotting. NRG-1 mRNA was present as bands of approximately 2, 3 and 6 kb. It was clearly detected in the prefrontal cortex (middle laminae), hippocampal formation (except CA1), cerebellum, oculomotor nucleus, superior colliculus, red nucleus and substantia nigra pars compacta. At the cellular level, NRG1 mRNA was abundant in hippocampal and cortical pyramidal neurons and some interneurons, and in cerebellar Purkinje cells and Golgi cells. NRG-1 protein was detected as bands of approximately 140, 110, 95 and 60 kD. Immunohistochemistry revealed NRG-1 in many cell populations, consistent with the mRNA data, being prominent in pyramidal neurons, Purkinje cells, several brainstem nuclei, and white matter neurons. Moderate NRG-1 immunoreactivity was also observed in cerebellar and dentate gyrus granule cells, and some glia. Within neurons, NRG-1 staining was primarily somatodendritic; in the cell body staining was granular, with clustering close to the plasma and nuclear membranes. There was also labeling of some fiber tracts, and local areas of neuropil (e.g. in the dentate nucleus) suggestive of a pre-synaptic location of NRG-1. The data show a widespread expression of NRG-1 in the adult human brain, including, but not limited to, brain areas and cell populations implicated in schizophrenia. Using these normative data, future studies can ascertain whether the role of NRG-1 in the disease is mediated, or accompanied, via alterations in its expression.
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PMID:Neuregulin-1 (NRG-1) mRNA and protein in the adult human brain. 1521 75

Several types of evidence suggesting that the inflammatory response system is associated with pathophysiology of schizophrenia have been accumulated. Recently, a prospective double-blind study demonstrated that supplementary treatment with celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, produced significantly greater improvement in scores on the Positive and Negative Syndrome Scale (PANSS) and on all subscales during the acute phase in patients with schizophrenia compared with risperidone alone therapy. The therapeutic effect of celecoxib on the psychopathology of schizophrenia is speculated to be based on COX activity inhibition; however, the detailed pharmacological mechanisms are unclear. To clarify whether or not COX-2 expression is altered in schizophrenia, we examined neuronal COX-2 expression in the hippocampus from cases of schizophrenia (n = 17), normal controls (n = 22), and cases of Alzheimer's disease (AD) as a positive control (n = 17). Quantitative immunohistochemical analysis demonstrated that neuronal COX-2 expression was significantly up-regulated in each CA1-4 region in Alzheimer's disease compared with controls, and that the mean COX-2 immunointensity in CA1-4 was significantly correlated with Abeta load in cases of Alzheimer's disease. In contrast, COX-2 expression was not up-regulated in any subdivision of the hippocampus in the schizophrenia group. These results suggest that celecoxib may affect the pathophysiology of schizophrenia through COX-2-independent actions rather than by inhibiting activity of up-regulated COX-2 protein.
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PMID:Neuronal expression of cyclooxygenase-2, a pro-inflammatory protein, in the hippocampus of patients with schizophrenia. 1527 98

A series of studies has shown that neonatal excitotoxic disconnection of the rat ventral hippocampus may serve as a heuristic model of schizophrenia. The model mimics a spectrum of neurobiologic and behavioural features of schizophrenia. It produces functional pathology in critical brain regions implicated in schizophrenia and connected with the hippocampal formation, namely, the striatum, nucleus accumbens and the prefrontal cortex. These brain regions are also targeted by antipsychotic drugs. Neonatal insult leads in young adulthood to the emergence of abnormalities in a number of dopamine-related behaviours. It also models some of the negative aspects of schizophrenia, such as social impairments and working memory deficits. Moreover, our data show that even transient inactivation of the ventral hippocampus during a critical period of development that produces subtle anatomical changes in the hippocampus may be sufficient to trigger behavioural changes similar to those observed in animals with the permanent excitotoxic lesion. The results of bromodeoxyuridine (BrdU) incorporation studies show that this transient disconnection in the CA1 and CA2 area of the hippocampus may have long-lasting consequences for neurogenesis in the dentate gyrus. Our data suggest that neonatal disconnection of the ventral hippocampus alters development and plasticity of prefrontal cortical circuitry and produces a constellation of behavioural and cellular changes that mimic many aspects of schizophrenia. The neonatal hippocampal disconnection model represents a potential new model of schizophrenia without a gross anatomical lesion.
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PMID:Using animal models to test a neurodevelopmental hypothesis of schizophrenia. 1530 44

Several lines of evidence have pointed to a role of the dopamine system in the pathophysiology of schizophrenia. A recent postmortem study demonstrated a selective decrease of tyrosine hydroxylase fibers on pyramidal neurons in sector CA2 in the hippocampus of schizophrenics. Although both brain imaging and postmortem studies have examined the distribution of the D1 receptor in the prefrontal and cingulate cortex, no study to date has examined its expression of mRNA using a high-resolution autoradiographic approach. In order to further assess whether the regulation of the dopamine D1 receptor is altered in hippocampal neurons in this disorder, we used in situ hybridization (ISH) to measure the expression of messenger RNA for this receptor in the dentate gyrus and sectors CA1-4. Both the number of cells expressing D1 mRNA and the amount of expression per cell were measured in 15 schizophrenic, 15 bipolar disorder, and 15 normal control subjects. The results show a significant (21%) and selective decrease in D1 mRNA expression in sector CA3 of schizophrenic subjects. First-degree relatives of schizophrenics did not show any differences in either the expression of D1 mRNA per cell or the number of cells expressing this mRNA when compared to a separate group of normal controls matched for age and PMI. Subjects with bipolar disorder also showed a significant (25%) and selective increase of D1 mRNA expression in sector CA2. Other hippocampal sectors did not show significant changes. These findings in schizophrenics and bipolars were also associated with inverse changes in the overall number of neurons expressing D1 mRNA in sectors CA3 and CA2, respectively. This study shows diagnosis-specific changes in D1 mRNA expression in the hippocampus of schizophrenic versus bipolar subjects and suggests that this neuromodulatory system may show distinct changes in the pathophysiology of the two disorders.
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PMID:Differences in the cellular distribution of D1 receptor mRNA in the hippocampus of bipolars and schizophrenics. 1545 63

Birth complications involving fetal hypoxia and stress at adulthood, which are risk factors for schizophrenia, can produce alterations in subcortical dopamine (DA) function in rat models. As adults, rats born either by cesarean section (C-section) or by C-section with added global anoxia show increased stress-induced DA release from nucleus accumbens and increased amphetamine-induced locomotion, compared to vaginally born controls. Moreover, stress at adulthood interacts with these birth insults to modulate DA receptor and transporter levels. Glutamatergic transmission at the level of the nucleus accumbens, prefrontal cortex, and hippocampus are known to modulate subcortical DA activity. Thus, altered excitatory amino acid (EAA) function might contribute to the dopaminergic changes observed in rats after birth insult and/or stress at adulthood. To test this possibility, rats born vaginally, by C-section, or by C-section with 15 min of anoxia, were either repeatedly stressed (15 min of tail pinch daily for 5 days) at adulthood or received no stress, and levels of EAA receptor binding were measured by ligand autoradiography in limbic brain regions. As adults, rats born by C-section showed increases in AMPA receptor binding in nucleus accumbens shell, NMDA receptor binding in cingulate cortex, and kainate receptor binding in the hippocampal CA1 region. Anoxic rats showed increases in CA1 kainate receptor and anterior olfactory NMDA receptor binding. Stress at adulthood increased AMPA receptor binding in several regions of prefrontal cortex and reduced NMDA receptor binding in infralimbic cortex and dentate gyrus, across all birth groups. Two instances of interactions between birth insult and stress at adulthood were observed. Stress reduced cingulate cortex NMDA receptor binding and increased olfactory tubercle kainate receptor binding only in C-sectioned animals, but not in controls. The possibility that the observed EAA receptor changes contribute to dopaminergic dysfunction in these animal models is discussed, in light of known glutamate-DA interactions.
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PMID:Effects of birth insult and stress at adulthood on excitatory amino acid receptors in adult rat brain. 1545 66

Dopaminergic pathways have been recognized to play a critical role in cognition and emotion. Dopamine D2 and D4 receptors are the target for most common antipsychotics and their activation, particularly those in the medial temporal lobe structures, has been associated with their beneficial actions. The entorhinal cortex, which is the cortical area most consistently and severely affected in schizophrenia constitutes the main input to the hippocampus. Since the D4 receptor is highly concentrated in the hippocampus, and the effects of the selective activation of D4 receptors on the input/output function of the hippocampal formation are poorly understood, we sought to investigate the role of these receptors in the synaptic transmission and paired-pulse inhibition from the perforant path to area CA1 and the dentate gyrus. The D4 receptor antagonist, clozapine, translated paired-pulse inhibition into paired-pulse potentiation in both perforant path targets. By contrast, the D2/D3 antagonist quinpirole had no effect. The blockade of the D2/3 receptors with sulpiride, and of D1/5 receptors with SCH-23390, has no effect on paired-pulse inhibition, suggesting that these receptors are not involved in feedforward inhibition in these hippocampal areas. Interestingly, the perfusion of the D4 selective antagonist, L-745,870 (Patel et al., 1997: J Pharmacol Exp Ther 283:636-647) during the blockade of D2/3 and D1/5 receptors produces a reversible decrease in paired-pulse inhibition in CA1, but not in the DG. Our results show that endogenous DA tonically modulates feedforward inhibition in area CA1 and the dentate gyrus through the activation of D4 receptors located in the interneuronal population of these hippocampal regions. Since activation of the D4 receptor inhibits GABA release and GABAergic synaptic transmission, we suggest that the perforant path stimulates interneurons that have the D4 receptor and that, in turn, contact other interneurons that synapse onto pyramidal cells. (c) 2004 Wiley-Liss, Inc.
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PMID:Tonic modulation of inhibition by dopamine D4 receptors in the rat hippocampus. 1547 61

Methamphetamine (MAP), the most frequently abused substance in Japan, causes severe drug dependence and psychosis, similar to schizophrenia. It is suggested that long-term alterations in gene expression is related to MAP-induced brain dysfunction, including dependence and psychosis. DNA (cytosine-5) methyltransferase (Dnmt), a methylating enzyme of cytosine residues on CpG-dinucleotides, plays an important role in X chromosome inactivation, genomic imprinting, and gene expression. Reelin is an extracellular matrix protein secreted by GABAergic interneurons. Heterozygous reeler mice that exhibit a 50% downregulation of reelin expression replicate the dendritic spine and GABAergic defects described in schizophrenia. DNA methylation plays an important role in the epigenetic modification of reelin expression. We previously found that MAP could alter expression of Dnmt1 mRNA in the rat brain. In this study, we examined the brain mRNA for Dnmt2 and reelin in MAP-treated Wistar rats. Acute MAP (4 mg/kg) treatment significantly decreased Dnmt2 mRNA by 27% to 39% in hippocampus dentate gyrus, CA1, and CA3 24 h after treatment, and significantly decreased reelin mRNA by 28% in frontal cortex 3 h after treatment. These results suggest that (1) MAP can alter DNA methylation as well as expression of genes in these brain regions, and (2) decrease in reelin mRNA in the frontal cortex is similar to heterozygous reeler mice, which might be related to schizophrenia-like psychotic symptoms of MAP psychosis.
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PMID:Psychostimulant alters expression of DNA methyltransferase mRNA in the rat brain. 1554 6

The hippocampus is thought to play an important role in learning and memory processing, and impairments in memory, attention, and decision making are found commonly in schizophrenia. Although many studies have reported decreases in hippocampal volume in the left hemisphere in schizophrenia, regionally specific hippocampal volume loss has not been revealed consistently using volume analysis. Recently, many studies have analyzed shape asymmetry using 3-D models; however, inconsistent results have been reported, mainly due to methodologic differences. We therefore used an active, flexible, deformable shape model for surface parameterization, and compared shape asymmetry based on principal component analysis (PCA) in the hippocampi of schizophrenic patients with those of the normal controls. Although the overall pattern of the statistical results did not change according to the number of principal components, the reconstructed results based on six major components were much more distinguishable. Although the left hemispheric hippocampal volume was larger than the right hemispheric was in this study, the difference was not significant. In shape asymmetry analysis, the right hemisphere hippocampus was bilaterally larger than the left hemisphere hippocampus was in the head of the superior CA1 and smaller in the tail and head of the inferior CA1. The asymmetry in the schizophrenia group was statistically smaller than that in the control group through reduction of the left hemisphere hippocampus volume.
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PMID:Asymmetry analysis of deformable hippocampal model using the principal component in schizophrenia. 1585 83

We identified CAT 53 by cDNA hybridization selection as an expressed sequence tag (EST), located in the vicinity of HLA-C and designated as CAT (for HLA-C associated transcript) 53. CAT 53 encodes a protein described by others and commonly known as phosphatase 1 nuclear targeting subunit (PNUTS). PNUTS is a potent inhibitor of nuclear serine/threonine protein phosphatase 1 (PP1). We present the genomic organization of CAT 53, localize specific sites of mRNA transcription in thin sections of mouse brain by in-situ hybridization, and perform a structural analysis of the peptide domains. We also characterize the protein expression pattern for PNUTS by Western blotting and immunohistochemistry with PNUTS antibody in Alzheimer's disease (AD) brains and age-matched control brains. In-situ hybridization and immunohistochemistry analysis of human and mouse brain show high CAT 53 expression in the olfactory cortex, piriform cortex, and hippocampus. Very high expression of CAT 53 was found mainly in the hippocampus, frontal, and entorhinal cortex of control brains and in the neurofibrillary tangles of AD brain. In the hippocampus, CAT 53 is expressed in CA1 and CA3 cell layers and in the dentate gyrus. The hippocampus is known to play a fundamental role in learning and episodic memories and has been implicated in a number of neurological and psychiatric disorders, including AD, epilepsy, and schizophrenia. Our findings suggest that PNUTS, encoded by CAT 53 on 6p21.3, may have a role in the progression of AD.
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PMID:CAT 53: a protein phosphatase 1 nuclear targeting subunit encoded in the MHC Class I region strongly expressed in regions of the brain involved in memory, learning, and Alzheimer's disease. 1589 2

AMPA receptor potentiating drugs (e.g. ampakines) enhance glutamatergic neurotransmission, and may have potential therapeutic consequences in CNS disorders. The neuroanatomical basis of action for these compounds is at present unclear. This study aimed to identify the effects of two novel ampakines, Org 26576 and Org 24448, on local cerebral glucose use (LCGU) in the mouse. C57BL/6J mice received Org 26576 (0.1, 1, 10 mg/kg i.p.) or Org 24448 (3, 10, 30 mg/kg i.p.) or vehicle and LCGU was assessed using 14C-2-deoxyglucose autoradiography. Both compounds produced dose-dependent increases in LCGU with specific regional activation at low doses. Org 26576 (1 mg/kg) produced significant increases in 9 of the 43 areas examined, including the anteroventral and laterodorsal thalamus, cingulate cortex, dentate gyrus and CA3 subfield of the hippocampus. Org 24448 (3 mg/kg) produced significant increases in LCGU in 4 of the 43 regions examined, including the dorsal raphe nucleus, medial lateral habenula, CA1 subfield of the hippocampus and median forebrain bundle. Furthermore, the increases in LCGU observed with both Org 26576 (10 mg/kg) and Org 24448 (10 mg/kg) were blocked by pre-treatment with the AMPA receptor antagonist NBQX (10 mg/kg). These data demonstrate that both Org 26576 and Org 24448 produce dose-dependent AMPA receptor mediated increases in LCGU and provide an anatomical basis suggestive that these drugs may be of use in the treatment of conditions such as depression or schizophrenia.
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PMID:Regionally selective and dose-dependent effects of the ampakines Org 26576 and Org 24448 on local cerebral glucose utilisation in the mouse as assessed by 14C-2-deoxyglucose autoradiography. 1599 47


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