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)

Translation of human genetic mutations into genetic mouse models is an important strategy to study the pathogenesis of schizophrenia, identify potential drug targets, and test new drugs for new antipsychotic treatments. Although it is impossible to recapitulate the full spectrum of schizophrenia symptoms in animal models, hypothesis-driven genetic mouse models have been successful in reproducing several schizophrenia-like behaviors and uncovering the roles of specific genes in dopamine and glutamine neurotransmission systems in mediating schizophrenia-like behaviors. Recent discoveries of susceptibility genes for schizophrenia and recognition of cognitive dysfunction as a core feature of schizophrenia and a phenotype of susceptibility for schizophrenia offer opportunities to develop newer genetic mouse models based on susceptibility. This new generation of genetic mouse models could shed light on the etiology of schizophrenia and lead us to new hypotheses, novel diagnostic tools, and more effective therapy.
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PMID:Genetic mouse models of schizophrenia: from hypothesis-based to susceptibility gene-based models. 1663 Nov 33

Neurospectroscopy allows biochemical processes in the brain to be studied non-invasively. At magnetic field strengths of 1.5 T or higher, cerebral proton neurospectroscopy allows the ascertainment of values of myo-inositol, choline-containing compounds, creatine, glutamate, glutamine, and N-acetyl aspartate. At similar field strengths, cerebral 31-phosphorus neurospectroscopy allows the ascertainment of values of phosphomonoesters, inorganic phosphate, phosphodiesters, phosphocreatine, and the gamma, alpha and beta nucleotide triphosphate (mainly adenosine triphosphate) resonances. Since choline is a common polar head group at the Sn3 position of membrane phospholipid molecules, a raised level of free choline, as indexed by proton neurospectroscopy, can indicate relatively low anabolism of membrane phospholipid molecules. Furthermore, the choline peak includes phosphorylcholine and glycerophosphorylcholine and even ethanolamine. The phosphomonoesters peak measured using 31-phosphorus spectroscopy includes major contributions from phosphocholine, phosphoethanolamine and L-phosphoserine, which are important precursors of membrane phospholipids, while the phosphodiesters peak includes contributions from glycerophosphocholine and glycerophosphoethanolamine, which are important products of membrane phospholipid catabolism. Hence proton neurospectroscopy and 31-phosphorus neurospectroscopy can yield important information relating to the metabolism of cerebral membrane phospholipids. The application of these techniques to the investigation of membrane phospholipid metabolism in schizophrenia, depression, chronic fatigue syndrome (myalgic encephalomyelitis or M.E.) and dyslexia is described.
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PMID:Proton and 31-phosphorus neurospectroscopy in the study of membrane phospholipids and fatty acid intervention in schizophrenia, depression, chronic fatigue syndrome (myalgic encephalomyelitis) and dyslexia. 1677 68

Involvement of the prefrontal cortex in schizophrenia has been implicated by neuropsychological, as well as neuropathological and imaging studies. Reductions of N-acetylaspartate (NAA), an in vivo marker of neuronal integrity, have repeatedly been detected in the frontal lobes of patients with schizophrenia by proton magnetic resonance spectroscopy (1H-MRS). In chronic medicated patients, a positive correlation between NAA levels of the prefrontal cortex and cognitive functioning has been observed, but to date, there have been no studies in first-episode neuroleptic-naive patients. In this study, single-voxel 1H-MRS was used to investigate neuronal function of the dorsolateral prefrontal cortex in 15 first-episode and 20 chronic schizophrenic patients. Outcomes were compared to 20 age-matched healthy controls to assess the relationship between prefrontal metabolism and neuropsychological performance. Patients with chronic schizophrenia had significant reductions of NAA, glutamate/glutamine, and choline levels compared to first-episode patients and healthy controls. Furthermore, creatine and phosphocreatine were significantly reduced in both patient groups compared to healthy controls. In the neuropsychological tests, chronic schizophrenic patients performed significantly poorer in the Auditory Verbal Learning Task (AVLT) compared to first-episode patients. In both patient groups, NAA levels of the left frontal lobe significantly correlated with performances in verbal learning and memory. These results corroborate data from recent structural and spectroscopic imaging studies of the frontal lobes in schizophrenia, in which cortical gray matter reductions after onset of symptoms as well as reduced levels of NAA in chronic, but not in first-episode schizophrenic patients have been reported.
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PMID:Cognitive impairment and in vivo metabolites in first-episode neuroleptic-naive and chronic medicated schizophrenic patients: a proton magnetic resonance spectroscopy study. 1694 99

Clinical trials demonstrated that D-serine administration improves schizophrenia symptoms, raising the possibility that altered levels of endogenous D-serine may contribute to the N-methyl D-aspartate receptor hypofunction thought to play a role in the disease. We hypothesized that cerebro-spinal fluid (CSF) D-serine levels are decreased in the patients due to reduced synthesis and/or increased degradation in brain. We now monitored amino acid levels in CSF from 12 schizophrenia patients vs. 12 controls and in postmortem parietal-cortex from 15 control subjects and 15 each of schizophrenia, major-depression and bipolar patients. In addition, we monitored postmortem brain serine racemase and D-amino acid oxidase protein levels by Western-blot analysis. We found a 25% decrease in D-serine levels and D/L-serine ratio in CSF of schizophrenia patients, while parietal-cortex D-serine was unaltered. Levels of L-serine, L-glutamine and L-glutamate were unaffected. Frontal-cortex (39%) and hippocampal (21%) serine racemase protein levels and hippocampal serine racemase/D-amino acid oxidase ratio (34%) were reduced. Hippocampal D-amino-acid-oxidase protein levels significantly correlated with duration of illness (r=0.6, p=0.019) but not age. D-amino acid oxidase levels in patients with DOI>20 years were 77% significantly higher than in the other patients and controls. Our results suggest that reduced brain serine racemase and elevated D-amino acid oxidase protein levels may contribute to the lower CSF D-serine levels in schizophrenia.
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PMID:A CSF and postmortem brain study of D-serine metabolic parameters in schizophrenia. 1715 77

In mice, the deletion of the STOP protein leads to hyperdopaminergia and major behavioral disorders that are alleviated by neuroleptics, representing a potential model of schizophrenia. The reduction of the glutamatergic synaptic vesicle pool in the hippocampus could reflect a disturbance in glutamatergic neurotransmission in this model. Here we examined potential disturbances in energy metabolism and interactions between neurons and glia in 15-week-old STOP KO, wild-type, and heterozygous mice. Animals received [1-(13)C]glucose and [1,2-(13)C]acetate, the preferential substrates of neurons and astrocytes, respectively. Extracts from the whole forebrain and midbrain were analyzed by HPLC, (13)C and (1)H NMR spectroscopy. Amounts and labeling of most metabolites were unchanged. However, glutamine concentration and amount of [4,5-(13)C]glutamine derived from [1,2-(13)C]acetate significantly decreased by 17% and 18%, respectively, in STOP KO compared with wild-type mice. The amount of [4-(13)C]glutamate was decreased in STOP KO and heterozygous compared with wild-type mice. gamma-Aminobutyric acid labeling was not influenced by the genotype. Because STOP-deficient mice have a lower synaptic vesicle density, less glutamate is released to the synaptic cleft, leading to decreased stimulation of the postsynaptic glutamate receptors, reflecting increased glutamine metabolism only in the vicinity of the postsynapse of STOP KO mice.
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PMID:Hypoglutamatergic activity in the STOP knockout mouse: a potential model for chronic untreated schizophrenia. 1730 67

The anterior cingulate region is thought to be dysfunctional in schizophrenia, but whether this is the result of reduced neuronal integrity or changes in neurotransmitter systems remains an issue of debate. Fifteen male patients with schizophrenia and 14 male controls were assessed using proton magnetic resonance spectroscopy, with regions of interest placed in the right and left dorsal and rostral cingulate. The metabolites of interest were N-acetylaspartate (NAA), a putative neuronal marker, and glutamate + glutamine (Glx), which may index synapse number. Schizophrenia patients had lower NAA concentrations throughout the dorsal and rostral portions of the anterior cingulate and in both hemispheres, but showed no changes in Glx. Anterior cingulate involvement in schizophrenia is likely to be a result of neuronal loss or dysfunction.
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PMID:Evidence for neuronal dysfunction in the anterior cingulate of patients with schizophrenia: a proton magnetic resonance spectroscopy study at 3 T. 1757 88

Hypoxic-ischaemic (HI) encephalopathy is a severe complication of perinatal asphyxia and remains a frequent cause of a variety of brain disorders with long-term effects on the patients' life. The associated brain damage is strongly related to the toxic action of excitatory amino acids, especially glutamate and aspartate. Lamotrigine is an anti-epileptic drug that blocks the voltage-gated sodium channels of the presynaptic neuron and inhibits the release of glutamate. In the present study a well-established model of perinatal asphyxia in 7-d-old rats was used to investigate the effect of lamotrigine on HI-induced damage to different hippocampal brain structures, since disruption of this brain area is thought to play a key role in schizophrenia and epilepsy. Therefore, a combination of ischaemia, induced by unilateral occlusion of the left common carotid artery, followed by exposure to a 1-h period of hypoxia, was carried out in neonatal 7-d-old rats. Immediately after the insult, lamotrigine was given i.p. The histological outcome in the hippocampus was conducted and the tissue levels of glutamate, aspartate, GABA, and glutamine in the same area were determined. A remarkable reduction of HI-evoked damaged neurons in most of the investigated hippocampal regions was noted after lamotrigine administration. Furthermore, lamotrigine decreased the asphyxia-induced hippocampal tissue levels of glutamate and aspartate. Immediately after perinatal asphyxia GABA levels were enhanced, while levels of glutamine were decreased. Lamotrigine administration did not affect either GABA or glutamine levels. These results suggest a neuroprotective effect of lamotrigine in this particular animal model of neonatal HI encephalopathy.
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PMID:Neuroprotection by lamotrigine in a rat model of neonatal hypoxic-ischaemic encephalopathy. 1789 82

Altered expression of structural and functional molecules expressed by astrocytes may play a role in the pathophysiology of schizophrenia. We investigated the hypothesis that the astrocytic enzyme glutamine synthetase, involved in maintaining the glutamate-glutamine cycle, and the cytoskeletal molecule glial fibrillary acidic protein (GFAP) are abnormally expressed in schizophrenia. We used Western blot analysis to measure levels of glutamine synthetase and GFAP in several brain regions of subjects with schizophrenia and a comparison group. We found that glutamine synthetase protein expression was significantly decreased in the superior temporal gyrus, and both glutamine synthetase and GFAP were significantly reduced in the anterior cingulate cortex in schizophrenia. Neither molecule demonstrated altered expression in the dorsolateral prefrontal cortex, primary visual cortex, or hippocampus. Chronic treatment with haloperidol did not alter the expression of these molecules in the rat brain, suggesting that our findings are not due to a medication effect. These data support an astrocytic component to the pathophysiology of schizophrenia and suggest that astrocytic molecules involved in enzymatic activity and cytoskeletal integrity may have a role in disease-related abnormalities in this illness.
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PMID:Cortical expression of glial fibrillary acidic protein and glutamine synthetase is decreased in schizophrenia. 1856 76

A change in the glutamatergic system is thought to play an important role in the pathophysiology of schizophrenia. The aim of this study was to investigate the changes in metabolites, including glutamate (Glu), in the anterior cingulate cortex (ACC) and the left basal ganglia (ltBG) of patients with chronic schizophrenia using proton magnetic resonance spectroscopy ((1)H-MRS). In addition, since gender differences in this illness were known, we examined the effects of gender on these metabolites. The (1)H-MRS was performed on the ACC and ltBG of 30 patients with schizophrenia and 25 healthy individuals who acted as the control group. The levels of Glu, glutamine (Gln), creatine plus phosphocreatine (Cre), myo-inositol (mI), N-acetylaspartate (NAA), and choline-containing compounds (Cho) were measured. Two-way analysis of variance revealed that the illness significantly affected the levels of Glu and mI in the ACC; both metabolites were lower in the patients with schizophrenia as compared to the control subjects. The results also revealed that gender significantly affected the level of Gln in the ACC and the levels of Cre and NAA in the ltBG; the level of Gln in the ACC were higher in male subjects versus female subjects, whereas Cre and NAA levels in the ltBG were lower in male subjects as compared to female subjects. These results confirmed a change in the glutamatergic system and suggested an involvement of mI in the pathophysiology of schizophrenia.
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PMID:Metabolite changes and gender differences in schizophrenia using 3-Tesla proton magnetic resonance spectroscopy (1H-MRS). 1909 53

The rate of smoking in patients with schizophrenia is higher than that in the general population. Nicotinic acetylcholine receptors (nAChR) are involved in the sensorimotor gating deficits in schizophrenia. We have revealed that nicotine ameliorates the disruption of the PPI, a model of sensorimotor gating, which is induced by apomorphine, a dopamine receptor agonist, but is not effective for the disruption of the PPI induced by phencyclidine, a glutamine NMDA receptor antagonist, in rats. Furthermore, the ameliorating effect of nicotine is antagonized by methyllycaconitine, a selective alpha7 nAChR antagonist. The effect of nocitine was also investigated in the stereotyped behavior induced by apomorphine, however, nicotine was found to have no significant effect. Considering these results, the ameliorating effect of the disruption of the PPI via alpha7 nAChR is therefore thought to be involved in dopaminergic systems. The dopaminergic systems involved in alpha7 nAChR may be different from the systems involved in stereotypy. In addition, this review describes the effects of the alpha7 nicotinic receptor agonists.
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PMID:[Nicotinic acetylcholine receptors are possible therapeutic targets for schizophrenia]. 1918 47


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