UMLS:C0036341 - FACTA Search

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Query: UMLS:C0036341 (schizophrenia)
60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A model of the CA3 region of the hippocampus was used to simulate the P50 auditory-evoked potential response to repeated stimuli in order to study the neuronal circuits involved in a sensory-processing deficit associated with schizophrenia. Normal subjects have a reduced P50 auditory-evoked potential amplitude in response to the second of two paired auditory click stimuli spaced 0.5 s apart. However, schizophrenic patients do not gate or reduce their response to the second click. They have equal auditory-evoked response amplitudes to both clicks. When schizophrenic patients were medicated with traditional neuroleptics, the evoked potential amplitude to both clicks increased, but gating of the second response was not restored or improved. Animal studies suggest a role for septohippocampal cholinergic activity in sensory gating. We used a computational model of this system in order to study the relative contributions of local processing and afferent activity in sensory gating. We first compared the effect of information representation as average firing rate to information representation as cell assemblies in order to evaluate the best method to represent the response of hippocampal neurons to the auditory click. We then studied the effects of nicotinic cholinergic input on the response of the network and the effect of GABA(B) receptor activation on the ability of the local network to suppress the test response. The results of our model showed that nicotinic cholinergic input from the septum to the hippocampus can control the flow of sensory information from the cortex into the hippocampus. In addition, postsynaptic GABA(B) receptor activation was not sufficient to suppress the test response when the interstimulus interval was 500 ms. However, presynaptic GABA(B) receptor activity may be responsible for the suppression of the test response at this interstimulus interval.
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PMID:Inhibitory control of sensory gating in a computer model of the CA3 region of the hippocampus. 1269 Apr 84

Apolipoprotein-D (apoD), a member of the lipocalin family of proteins, binds to arachidonic acid and cholesterol among other hydrophobic molecules. Recently, elevated apoD levels have been reported in the post-mortem brains, as well as plasma, of schizophrenic patients and in rodent brains after chronic treatment with clozapine (CLOZ). These findings and the evidence for altered membrane lipid metabolism in schizophrenia suggest that apoD may have a role in the pathophysiology of illness, and also in the differential clinical outcome following treatment with typical and atypical antipsychotic drugs. Here, we compared the effects of these antipsychotics on the expression of apoD in rat brain. Chronic treatment with typical antipsychotic, haloperidol (HAL) reduced apoD expression in hippocampus, piriform cortex and caudate-putamen (p = 0.027-0.002), whereas atypical antipsychotics, risperidone (RISP) and olanzapine (OLZ) increased (p = 0.051 to < 0.001 and p = 0.048 to < 0.001, respectively) apoD expression. In hippocampus, HAL-induced changes were present in CA1, CA3 and dentate gyrus, however, apoD levels in motor cortex were unchanged. There were also very dramatic effects of HAL on the neuronal morphology, particularly, cellular shrinkage and disorganization with the loss of neuropil. Post-treatment, either with RISP or OLZ, was very effective in restoring the HAL-induced reduction of apoD, as well as cellular morphology. Similarly, pre-treatments were also effective, but slightly less than post-treatment, in preventing HAL-induced reduction of apoD. The increased expression of apoD by atypical antipsychotics may reflect a novel molecular mechanism underlying their favorable effects compared with HAL on cognition, negative symptoms and extra-pyramidal symptoms in schizophrenia.
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PMID:Antipsychotic drugs differentially modulate apolipoprotein D in rat brain. 1291 17

Recently, the pathogenesis of schizophrenia has been investigated from the perspective of neurodevelopmental dysfunction theory. On the other hand, it has been indicated that neurotrophic factors, such as nerve growth factors, brain-derived neurotrophic factor (BDNF), and neurotrophin-3, are significantly involved in the development and functional differences of central nervous system (CNS). Some reports proposed that the dysfunction of these factors could explain the pathogenesis of schizophrenia possibly. In this study, the authors investigated immunohistochemically the distribution and/or morphology of BDNF and TrkB, its peculiar receptor, in the hippocampal formation of schizophrenic brain. As a result, BDNF-positive pyramidal cells in the CA2 and neurons in the CA3 and the field of the CA4 were intensely stained compared to those of normal control. Staining of TrkB-positive neurons showed a signet-ring like shape in the hippocampus of normal control brains. Such figures were not observed on staining of those neurons from schizophrenic brains. In the control cases, TrkB-immunopositive varicose fibers were frequently seen. Those observed differences between schizophrenic and normal cases may indicate the existence of dysfunction of BDNF and TrkB in schizophrenic brain, and this dysfunction may be one of the factors involved in the pathogenesis of schizophrenia.
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PMID:Immunohistochemical study of brain-derived neurotrophic factor and its receptor, TrkB, in the hippocampal formation of schizophrenic brains. 1292 13

The N-methyl-d-aspartate receptor plays a critical role in the formation and maintenance of synapses during brain development. In the rodent, changes in subunit expression and assembly of the heteromeric receptor complex accompany these maturational processes. However, little is known about N-methyl-d-aspartate receptor subunit expression during human brain development. We used in situ hybridization to examine the distribution and relative abundance of NR1, NR2A and NR2B subunit messenger ribonucleic acids in the hippocampal formation and adjacent cortex of 34 human subjects at five stages of life (neonate, infant, adolescent, young adult and adult). At all ages, the three messenger ribonucleic acids were expressed in all subfields, predominantly by pyramidal neurons, granule cells and polymorphic hilar cells. However, their abundance varied across ontogeny. Levels of NR1 messenger ribonucleic acid in CA4, CA3 and CA2 subfields were significantly lower in the neonate than all other age groups. In the dentate gyrus, subiculum and parahippocampal gyrus, NR2B messenger ribonucleic acid levels were higher in the neonate than in older age groups. NR2A messenger ribonucleic acid levels remained constant, leading to an age-related increase in NR2A/2B transcript ratio. We conclude that N-methyl-d-aspartate receptor subunit messenger ribonucleic acids are differentially expressed during postnatal development of the human hippocampus, with a pattern similar but not identical to that seen in the rodent. Changes in subunit composition may thus contribute to maturational differences in human hippocampal N-methyl-d-aspartate receptor function, and to their role in the pathophysiology of schizophrenia and other neurodevelopmental disorders.
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PMID:Expression of NMDA receptor NR1, NR2A and NR2B subunit mRNAs during development of the human hippocampal formation. 1295 18

The effects of neonatal exposure to excitotoxins on the development of interneurons have not been well characterized, but may be relevant to the pathogenesis of neuropsychiatric disorders. In this study, the excitotoxin, kainic acid (KA) was administered to rats at postnatal day 7 (P7) by intracerebroventricular (i.c.v.) infusion. At P14, P25, P40 and P60, Nissl staining and immunohistochemical studies with the interneuron markers, glutamic acid decarboxylase (GAD-67), calbindin-D28k (CB) and parvalbumin (PV) were performed in the hippocampus. In control animals, the total number of interneurons, as well as the number of interneurons stained with GAD-67, CB and PV, was nearly constant from P14 through P60. In KA-treated rats, Nissl staining, GAD-67 staining, and CB staining revealed a progressive decline in the overall number of interneurons in the CA1 and CA3 subfields from P14 to P60. In contrast, PV staining in KA-treated rats showed initial decreases in the number of interneurons in the CA1 and CA3 subfields at P14 followed by increases that approached control levels by P60. These results suggest that, in general, early exposure to the excitotoxin KA decreases the number of hippocampal interneurons, but has a more variable effect on the specific population of interneurons labeled by PV. The functional impact of these changes may be relevant to the pathogenesis of neuropsychiatric disorders, such as schizophrenia.
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PMID:Intracerebroventricular kainic acid administration to neonatal rats alters interneuron development in the hippocampus. 1451 96

There is decreased activity of glutamate carboxypeptidase II (GCP II) in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of patients with schizophrenia. GCP II hydrolzses N-acetyl-alpha L-aspartyl-L-glutamate (NAAG), a peptide in the mammalian brain that binds to the N-methyl D-aspartate (NMDA) receptor and a group II metabotropic glutamate receptor, both of which have been implicated in the pathophysiology of schizophrenia. We examined the expression of GCP II mRNA in the DLPFC, entorhinal cortex (ERC), and hippocampus in postmortem samples from patients with schizophrenia and normal controls using in situ hybridization followed by silver grain detection. GCP II mRNA was detected in glial cells. Glial-rich regions, specifically the DLPFC and ERC white matter and the molecular and polymorphic layers in the hippocampus, express high levels of GCP II mRNA. Given the earlier finding of decreased GCP II activity in brains of subjects with schizophrenia, we expected to find lower GCP II mRNA levels in schizophrenia. Contrary to this expectation, we found a significantly higher expression of GCP II mRNA in one of the brain areas examined, the hippocampal CA3 polymorphic region. This may reflect a compensatory increase to correct for the decreased activity of GCP II activity. Our findings support the notion that the hydrolysis of NAAG is disrupted in schizophrenia and that specific anatomical regions may show discrete abnormalities in GCP II synthesis.
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PMID:Glutamate carboxypeptidase II gene expression in the human frontal and temporal lobe in schizophrenia. 1456 Mar 19

Growing evidence indicates that the amygdala modulates hippocampal functions. To test the hypothesis that this modulation may involve long-lasting effects on interneuronal networks in the hippocampus, changes in the expression of neurochemical markers specific for different interneuronal subpopulations were assessed in adult rats 96 h following acute infusion of low doses of the GABAA receptor antagonist picrotoxin into the amygdala. The numerical density (Nd) of somata showing immunoreactivity (IR) for parvalbumin (PVB) was decreased in dentate gyrus (DG) and the CA4-2 region, while that of calretinin (CR)-IR was decreased in DG and CA2. The Nd of calbindin D28k (CB)-IR somata was decreased in CA3-2. The densities of axon terminals arising from PVB-IR and cholecystokinin (CCK)-IR basket neurons were also altered, with those of CCK-IR terminals increased across all sectors, while PVB-IR terminals were decreased only in the CA region. Increases in CCK-IR terminals were paralleled by increases of terminals with IR for the 65-kD isoform of glutamate decarboxylase (GAD65). Mixed-effects statistical models, adapted specifically for these analyses, indicated that perturbations of amygdalar inputs to the hippocampus significantly alter the drive that hippocampal PVB-, CR-, and CB-IR neurons within the dentate gyrus/CA4 region exercise on CCK-IR terminals within the same region as well as in CA3-1. These results suggest that amygdalar modulation of specific neuronal subpopulations may induce lasting and far-reaching changes in the hippocampus during normal functioning, as well as in diseases involving a disruption of amygdalar activity. In particular, changes in specific interneuronal markers within selective hippocampal sectors detected in the present results are strikingly similar to those reported in this region in schizophrenia. These similarities suggest that, in this disease, a disruption of GABAergic transmission within the amygdala may play a significant role in the induction of abnormalities in the hippocampus.
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PMID:Long-term effects of amygdala GABA receptor blockade on specific subpopulations of hippocampal interneurons. 1538 57

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

Schizophrenic patients are thought to have an impaired ability to process sensory information. This deficit leads to disrupted auditory gating measured electrophysiologically as a reduced suppression of the second of paired auditoryevoked responses (P50) and is proposed to be associated with decreased function and/or expression of the homomeric alpha7 nicotinic acetylcholine receptor (nAChR). Here, we provide evidence that N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride (PNU-282987), a novel selective agonist of the alpha7 nAChR, evoked whole-cell currents from cultured rat hippocampal neurons that were sensitive to the selective alpha7 nAChR antagonist methyllycaconitine (MLA) and enhanced GABAergic synaptic activity when applied to hippocampal slices. Amphetamine-induced sensory gating deficit, determined by auditory-evoked potentials in hippocampal CA3 region, was restored by systemic administration of PNU-282987 in chloral hydrate-anesthetized rats. Auditory gating of rat reticular thalamic neurons was also disrupted by amphetamine; however, PNU-282987 normalized gating deficit only in a subset of tested neurons (6 of 11). Furthermore, PNU-282987 improved the inherent hippocampal gating deficit occurring in a subpopulation of anesthetized rats, and enhanced amphetamine-induced hippocampal oscillation. We propose that the alpha7 nAChR agonist PNU-282987, via modulating/enhancing hippocampal GABAergic neurotransmission, improves auditory gating and enhances hippocampal oscillatory activity. These results provide further support for the concept that drugs that selectively activate alpha7 nAChRs may offer a novel, potential pharmacotherapy in treatment of schizophrenia.
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PMID:The selective alpha7 nicotinic acetylcholine receptor agonist PNU-282987 [N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride] enhances GABAergic synaptic activity in brain slices and restores auditory gating deficits in anesthetized rats. 1552 1

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

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