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)

Limbic cortical regions, including anterior cingulate cortex (ACC), prefrontal cortex (PFC) and entorhinal cortex (ERC), have been implicated in the neuropathology of schizophrenia. Glutamate projection neurons connect these limbic cortical regions to each other, as well as to the terminal fields of the striatal/accumbens dopamine neurons. Subsets of these glutamate projection neurons, and of the GABA interneurons in cortex, contain the neuropeptide cholecystokinin (CCK). In an effort to study the limbic cortical glutamate projection neurons and GABA interneurons in schizophrenia, we have measured CCK mRNA with in situ hybridization histochemistry in postmortem samples of dorsolateral (DL)PFC, ACC and ERC of seven schizophrenics, nine non-psychotic suicides and seven normal controls. CCK mRNA is decreased in ERC (especially layers iii vi) and subiculum in schizophrenics relative to controls. Cellular analysis indicates that there is a decrease in density of CCK mRNA in labelled neurons. In so far as ERC CCK mRNA is not reduced in rats treated chronically with haloperidol, this decrease in schizophrenics does not appear to be related to neuroleptic treatment. In contrast, in DLPFC, where schizophrenics do not differ from normals, the suicide victims have elevated CCK mRNA (especially in layers v and vi), and increased cellular density of CCK mRNA, relative to both normals and schizophrenics. These results lend further support for the involvement of ERC and hippocampus in schizophrenia, suggesting that neurons that utilize CCK may be particularly important. Similarly, an increase in CCK mRNA levels in the PFC of suicides adds to a growing body of evidence implicating this structure in this pathological state. In so far as CCK is co-localized with GABA or glutamate in cortical neurons, both of these neuronal populations need to be studied further in schizophrenia and suicide.
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PMID:Abnormal cholecystokinin mRNA levels in entorhinal cortex of schizophrenics. 927 88

Several kinds of psychiatric symptoms (anxiety, depression, schizophrenia) have been associated with epilepsies, and clinical data suggest that patients with seizures involving limbic structures are the most prone to develop behavioural disorders between the seizures (i.e. interictally). Studying the neurobiological mechanisms that underlie these symptoms is difficult in humans because of different interfering factors (e.g. psychosocial difficulties, pharmacological side-effects, lesions), which can be avoided in animal models. Using repetitive electrical stimulations (kindling) or local applications of a neuroexcitotoxin in limbic structures (mainly the amygdala and hippocampus), several authors have reported lasting changes of emotional reactivity in cats and rats. These changes appear as anxiety-related reactions expressed as a hyperdefensiveness in the cat, or a reduction of spontaneous exploration in tests predictive of anxiogenic effects in the rat. Some neuroplasticity processes known to develop during epileptogenesis (neuronal-hyperexcitability, modulation of GABA/benzodiazepine transmission) may participate in these lasting changes of behaviour, especially in structures involved in the control of fear-promoted reactions (amygdala, periaqueductal grey matter). In addition, endogenous control systems may also play a critical role in the occurrence of interictal behavioural disorders.
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PMID:Anxiogenic-like consequences in animal models of complex partial seizures. 941 1

The largest cluster of positive results, considering both bipolar and schizophrenia, occurs in the 4p region that includes D4S394 and DRD5. Four groups report at least weakly positive linkage analyses this region for bipolar disorder, and two groups find weak positive allelic association with schizophrenia in the region, although at separate markers. On the other hand, at least five groups do not find evidence for linkage of bipolar disorder to this area of 4p. The pattern on 4q is less clear, with a mixture of negative and small positive results in either bipolar or schizophrenia families. Additional allelic association and TDT studies of 4p markers in bipolar disorder and in schizophrenia might be able to narrow the focus of the 4p investigations. The dopamine D5 receptor gene has seductive qualities as a candidate gene because of the pharmacology of psychotic disorders. It would be helpful to have additional markers developed close to or in the recoding region of DRD5 in order to have the extra information at the DNA level provided by haplotype analysis. Chromosome 4 susceptibility loci may figure prominently in alcoholism, although a great deal of work remains to be done. With just two groups reporting here, only a limited assessment of the overall effect of the ADH cluster and the GABA cluster is possible. However, these loci have merit as candidate genes, and thus further work on the current and additional families is clearly indicated.
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PMID:Chromosome 4 workshop. 968 26

Amino acid (glutamatergic, GABAergic) neuron deficiency theories of schizophrenia offer plausible explanations of pathogenesis. However, reports of disease-related reductions in amino acid synthesizing enzymes in post-mortem brains are contradictory. We measured neuronal uptake sites for gamma-aminobutyric acid (GABA; [3H]nipecotic acid binding) and nerve terminal/glial uptake sites for L-glutamate (D-[3H aspartate binding) in three independent groups of post-mortem brains from patients with schizophrenia and control subjects. Measurements were also made of the phencyclidine site of the glutamate N-methyl-D-aspartate (NMDA) receptor. Samples from patients showed no reductions in the binding of [3H]nipecotic acid or D-[3H]aspartate in caudate, putamen or globus pallidus. On the contrary, some increased binding of both ligands was observed in patients in many comparisons with controls. There were no clear-cut changes in NMDA receptor binding. The most consistent change in the brain sets was increased [3H]nipecotic acid binding in caudate-putamen. This could be due to neuroleptic treatment. The findings produce no evidence that schizophrenia involves major loss of GABA neuron terminals in the basal ganglia or losses of corticostriatal glutamatergic projections.
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PMID:Absence of basal ganglia amino acid neuron deficits in schizophrenia in three collections of brains. 968 21

GABA (gamma-amino-butyric acid) receptors are a family of proteins involved in the GABAergic neurotransmission of the mammalian central nervous system (CNS). They have physiological importance and clinical relevance in several diseases. We report the identification, cloning, and fine mapping of the human cDNA for GABAB receptor. A 4.2-Kb cDNA containing an open reading frame for a predicted protein of 960 aa was isolated from a fetal brain cDNA library. It had a strong identity (91.5%) with the rat GABAB receptor (rGB1A) nucleotide sequence, that corresponded to 98.6% identity at the amino acid level. Expression of the GABAB at the transcription level was detected by Northern analysis in all brain areas examined. The GABAB receptor has been mapped to human chromosome 6p21.3 within the HLA class I region close to the HLA-F gene. Susceptibility loci for multiple sclerosis, epilepsy, and schizophrenia have been suggested to map in this region.
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PMID:GABA (gamma-amino-butyric acid) neurotransmission: identification and fine mapping of the human GABAB receptor gene. 975 14

Dual probe microdialysis was employed in intact rat brain to investigate the effect of intrastriatal perfusion with selective dopamine D1 and D2 receptor agonists and with c-fos antisense oligonucleotide on (a) local GABA release in the striatum; (b) the internal segment of the globus pallidus and the substantia nigra pars reticulata, which is the output site of the strionigral GABA pathway; and (c) the external segment of the globus pallidus, which is the output site of the striopallidal GABA pathway. The data provide functional in vivo evidence for a selective dopamine D1 receptor-mediated activation of the direct strionigral GABA pathway and a selective dopamine D2 receptor inhibition of the indirect striopallidal GABA pathway and provides a neuronal substrate for parallel processing in the basal ganglia regulation of motor function. Taken together, these findings offer new therapeutic strategies for the treatment of dopamine-linked disorders such as Parkinson's disease, Huntington's disease, and schizophrenia.
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PMID:Functional neuroanatomy of the basal ganglia as studied by dual-probe microdialysis. 986 60

Here we have described a novel excitotoxic process in which hypofunctional NMDA receptors cease driving GABA ergic neurons which cease inhibiting excitatory transmitters in the brain. These disinhibited excitatory transmitters then act in concert to slowly hyperstimulate neurons in corticolimbic brain regions. We have discussed how such an abnormality could exist in the brains of individuals with schizophrenia or AD and could account for the clinical stigmata of the two disorders. In addition, we have highlighted how other disorder-specific factors would account for the differences in the clinical presentation of AD and schizophrenia. In an animal model, pharmacological methods have been developed for preventing the overstimulation of these vulnerable corticolimbic pyramidal neurons and at least some of these methods may be applicable for treating AD and schizophrenia.
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PMID:The glutamate synapse in neuropsychiatric disorders. Focus on schizophrenia and Alzheimer's disease. 993 93

Phencyclidine (PCP) is a drug of abuse that produces schizophrenia-like symptoms in humans and increases locomotor activity and stereotypic behavior in rodents. PCP-induced alteration in rat locomotor activity is thought to be mediated by an inhibition of N-methyl-D-aspartate (NMDA) receptors in the striatum and other brain regions. In this study, rats treated chronically with PCP (20 mg/kg once per day for 5 days) showed a marked increase in locomotor activity following a PCP challenge (3.2 mg/kg) administered after either 3 or 8 days of withdrawal. In biochemical assays, the release of striatal [14C]GABA by NMDA was enhanced by about 77% by chronic PCP treatment, whereas [3H]ACh release was increased by about 31% in tissue from PCP-treated rats. Even though binding experiments with 1-[1-(2-thiethyl)cyclohexyl]piperidyl-3,4 3H(N) ([3H]TCP) showed no alteration in the Kd or Bmax in whole striatum, quantitative immunocytochemical experiments found an upregulation in the NR1 subunit in the cell bodies and neuropil of cortical and striatal regions of the forebrain following chronic PCP treatment. An increase in the size of NR1-immunoreactive cells in the forebrain was also observed following chronic PCP treatment. Together, these data may help in understanding the mechanisms underlying the adaptive response to chronic reduction in glutamatergic NMDA transmission that has been postulated to be involved in the etiology of schizophrenia.
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PMID:Augmentation of locomotor activity by chronic phencyclidine is associated with an increase in striatal NMDA receptor function and an upregulation of the NR1 receptor subunit. 1002 41

Having shown a decrease in serotonin2A receptors in the dorsolateral prefrontal cortex (DLPFC) from schizophrenic subjects, we have now determined if this change was reflective of widespread changes in neurochemical markers in DLPFC in schizophrenia. In Brodmann's area (BA) 9 from 19 schizophrenic and 19 control subjects, we confirmed a decrease in the density of [3H]ketanserin binding to serotonin2A receptors in tissue from the schizophrenic subjects [39 +/- 3.3 vs. 60 +/- 3.6 fmol/mg estimated tissue equivalents (ETE); p < 0.005]. In addition, the density of [3H]muscimol binding to GABA(A) receptors was increased in the schizophrenic subjects (526 +/- 19 vs. 444 +/- 28 fmol/mg ETE; p < 0.02). [3H]YM-09151-2, N-[1-(2-thienyl)cyclohexyl]-3,4-[3H]piperidine, [3H]SCH 23390, [3H]mazindol, and N(G)-nitro-L-[3H]arginine binding to BA 9 did not differ between groups, and there was no specific binding of [3H]raclopride or 7-hydroxy-2-(di-n-[3H]propylamino)tetralin to BA 9 from either cohort of subjects. This suggests the density of dopamine D1-like and NMDA receptors, the dopamine transporter, and nitric oxide synthase activity are not altered in BA 9 from schizophrenic subjects. The selective nature of the changes in serotonin2A and GABA(A) receptors in DLPFC could indicate that these changes are involved in the pathology of schizophrenia.
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PMID:Changes in serotonin2A and GABA(A) receptors in schizophrenia: studies on the human dorsolateral prefrontal cortex. 1009 66

Despite a hundred years' research, the neuropathology of schizophrenia remains obscure. However, neither can the null hypothesis be sustained--that it is a 'functional' psychosis, a disorder with no structural basis. A number of abnormalities have been identified and confirmed by meta-analysis, including ventricular enlargement and decreased cerebral (cortical and hippocampal) volume. These are characteristic of schizophrenia as a whole, rather than being restricted to a subtype, and are present in first-episode, unmedicated patients. There is considerable evidence for preferential involvement of the temporal lobe and moderate evidence for an alteration in normal cerebral asymmetries. There are several candidates for the histological and molecular correlates of the macroscopic features. The probable proximal explanation for decreased cortical volume is reduced neuropil and neuronal size, rather than a loss of neurons. These morphometric changes are in turn suggestive of alterations in synaptic, dendritic and axonal organization, a view supported by immunocytochemical and ultrastructural findings. Pathology in subcortical structures is not well established, apart from dorsal thalamic nuclei, which are smaller and contain fewer neurons. Other cytoarchitectural features of schizophrenia which are often discussed, notably entorhinal cortex heterotopias and hippocampal neuronal disarray, remain to be confirmed. The phenotype of the affected neuronal and synaptic populations is uncertain. A case can be made for impairment of hippocampal and corticocortical excitatory pathways, but in general the relationship between neurochemical findings (which centre upon dopamine, 5-hydroxytryptamine, glutamate and GABA systems) and the neuropathology of schizophrenia is unclear. Gliosis is not an intrinsic feature; its absence supports, but does not prove, the prevailing hypothesis that schizophrenia is a disorder of prenatal neurodevelopment. The cognitive impairment which frequently accompanies schizophrenia is not due to Alzheimer's disease or any other recognized neurodegenerative disorder. Its basis is unknown. Functional imaging data indicate that the pathophysiology of schizophrenia reflects aberrant activity in, and integration of, the components of distributed circuits involving the prefrontal cortex, hippocampus and certain subcortical structures. It is hypothesized that the neuropathological features represent the anatomical substrate of these functional abnormalities in neural connectivity. Investigation of this proposal is a goal of current neuropathological studies, which must also seek (i) to establish which of the recent histological findings are robust and cardinal, and (ii) to define the relationship of the pathological phenotype with the clinical syndrome, its neurochemistry and its pathogenesis.
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PMID:The neuropathology of schizophrenia. A critical review of the data and their interpretation. 1021 75


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