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)

Prepulse inhibition (PPI) of the startle reflex is a measure of sensorimotor gating that is reduced in humans with certain neuropsychiatric disorders, including schizophrenia, and in rats after manipulations of limbic cortico-striato-pallido-pontine circuitry. We have reported that PPI is reduced after specific manipulations of the hippocampal complex (HPC) in rats, but the mechanisms for these effects remain poorly understood. For example, dopaminergic substrates clearly regulate PPI, but the PPI-disruptive effects of intra-HPC carbachol or NMDA are not reversed by D2 receptor antagonists. This study examined the anatomical specificity within the hippocampal complex of the PPI-disruptive effects of NMDA infusion. Startle magnitude and PPI were assessed after acute bilateral infusion of NMDA (0, 0.4 or 0.8 microg) into the dorsal subiculum (DS), region CA1, the ventral subiculum (VS), the rostral entorhinal cortex (ECr) and the caudal entorhinal cortex (ECc). A dorsal-ventral gradient for NMDA effects was observed, with a dose-dependent disruption of PPI after NMDA infusion into the VS or EC, but not the DS, and with intermediate level effects observed after NMDA infusion into CA1. A second set of studies confirmed that the failure of NMDA effects in the DS did not reflect site-related differences in startle magnitude or baseline levels of PPI. These findings demonstrate the importance of the ventral, but not the dorsal HPC, in the glutamatergic regulation of PPI.
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PMID:Regulation of sensorimotor gating in rats by hippocampal NMDA: anatomical localization. 1130 5

Recent postmortem studies have suggested that changes in the regulation of kainate-sensitive glutamate receptors (kainate receptors) in the hippocampus may play a role in schizophrenia. To explore this possibility further, the distribution of immunoreactivity (IR) for the GluR5,6,7 subunits of the KR was assessed in a cohort consisting of 15 normal controls, 15 schizophrenics, and 9 manic depressives matched for age and postmortem interval (PMI). Cross sections of hippocampus showed abundant GluR5,6,7-IR on apical dendrites of pyramidal neurons in the stratum radiatum and stratum moleculare. In normal controls, both the numerical and length density of IR dendrites were much higher in sector CA2 than in sectors CA3 or CA1. When data for the individual groups were separately examined, the schizophrenics showed a 30-35% reduction in the density of GluR5,6,7-IR dendrites found in both stratum radiatum and stratum moleculare of sectors CA3 and CA2, as well as proximal and middle portions of CA1. In CA2, the magnitude of this decrease in schizophrenia was 2.5 times larger than that seen in any of the other sectors. For the manic depressive group, no significant differences were observed in any sectors or laminae examined. The potential confounding effects of either age, PMI, or neuroleptic exposure do not explain the reduced density of IR dendrites detected in the schizophrenic group. Taken together, the preferential reduction of GluR5,6,7-IR observed on apical dendrites of pyramidal neurons is consistent with a functional downregulation of the kainate receptor in the hippocampus of schizophrenic brain.
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PMID:GluR5,6,7 subunit immunoreactivity on apical pyramidal cell dendrites in hippocampus of schizophrenics and manic depressives. 1173 2

Several lines of evidence have implicated prenatal stress and the hippocampal GABA system in the pathophysiology of schizophrenia, and prenatal stress is believed to increase the risk for schizophrenia through alterations of this neurotransmitter. To explore this hypothesis, we treated male rats pre- and/or postnatally (P48 and P60) with either corticosterone (CORT) or vehicle to establish three study groups: VVV, receiving vehicle at all three time points; VCC, receiving vehicle prenatally and CORT at both postnatal timepoints; and CCC, receiving CORT at all three timepoints. Animals were sacrificed at either 24 h or 5 days after final injection and examined for mRNA levels of GAD65, GAD67, and the GABA(A) receptor subunits alpha2 and gamma2. At 24 h, GAD65 mRNA was decreased in CA1, CA2, CA4, and dentate gyrus (DG) of VCC rats; this effect was either decreased or reversed in CCC-treated animals. No effect was detected in GAD67 mRNA at 24 h. At 5 days, CORT treatment increased GAD67 mRNA levels in CA1, CA3, and DG. Prenatal treatment with CORT was associated with increased responsiveness only in CA3 and DG. For the GABAA receptor, alpha2 subunit mRNA did not show any change in response to CORT treatment, while that for the gamma2 subunit was decreased in CA2 of both VCC- and CCC-treated animals. Consistent with gamma2 subunit mRNA decreases, benzodiazepine (BZ) receptor binding activity was decreased in CA2 with CORT treatment. Prenatal CORT exposure neither increased nor decreased this effect. These results demonstrate that CORT administration is associated with a complex regulation of mRNA expression for pre- and postnatal aspects of the hippocampal GABA system. Under these conditions, prenatal exposure to CORT may sensitize some of these effects, but does not fundamentally alter the nature of this response.
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PMID:Effects of pre- and postnatal corticosterone exposure on the rat hippocampal GABA system. 1173 3

Cytoarchitectural changes in the hippocampal formation have been prominent among the various neuropathological abnormalities reported in schizophrenia. Replicated positive findings include decreased neuronal size and alterations in presynaptic and dendritic markers. These findings, in the absence of neurodegenerative changes, suggest that there are alterations in the neural circuitry in schizophrenia. These may represent the anatomical correlate of the aberrant functional connectivity described in neuroimaging studies, which in turn contributes to the psychotic and cognitive symptomatology of the disorder. The identity of the affected hippocampal circuits remains unclear; there is evidence for both glutamatergic and GABAergic involvement, and perhaps for a gradient of pathology in which changes are most apparent in CA4 and the subiculum, and least in CA1. The data, their interpretation, and their limitations are discussed, with particular emphasis upon molecular and immunological studies of synaptic protein gene expression.
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PMID:Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia. 1173 4

NMDA antagonists provide the best pharmacological model of psychosis-related schizophrenia. Data from circuit analysis of the effects of the antagonism of NMDA receptors in the CA1 region of the hippocampus of rats in vitro suggest a hypothesis concerning cortical circuit dysfunction responsible for NMDA antagonist-dependent psychosis, relevant to the psychosis associated with schizophrenia. The NMDA antagonists may act by causing a selective, partial, disinhibition of cortical projection cells. The effects are partially due to the partial role of NMDA-dependent transmission in the excitatory glutamate drive of interneurons. Characterization of the selectivity is incomplete, but includes disinhibition of the recurrent inhibitory circuit and is concentration-sensitive. It may result from differences in NMDA receptors (NMDARs) on interneurons. At higher concentrations, antagonism of all NMDA-dependent transmission results in anesthesia. At low concentration, selective blockade of NMDA-dependent LTP of the recurrent inhibitory circuit may disrupt particular aspects of information processing involving learning and/or memory, consistent with the generation of abnormal associations. An endogenous peptide, NAAG, is shown to antagonize NMDARs in a manner similar to known psychotogenic agents like ketamine or phencyclidine. Finally, mechanisms that could enhance NMDAR function are discussed as possible therapeutic strategies for psychosis.
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PMID:Circuit analysis of NMDAR hypofunction in the hippocampus, in vitro, and psychosis of schizophrenia. 1173 9

In order to understand how the molecular or cellular defects that underlie a disease of the nervous system lead to the observable symptoms, it is necessary to develop a large-scale neural model. Such a model must specify how specific molecular processes contribute to neuronal function, how neurons contribute to network function, and how networks interact to produce behavior. This is a challenging undertaking, but some limited progress has been made in understanding the memory functions of the hippocampus with this degree of detail. There is increasing evidence that the hippocampus has a special role in the learning of sequences and the linkage of specific memories to context. In the first part of this paper, we review a model (the SOCRATIC model) that describes how the dentate and CA3 hippocampal regions could store and recall memory sequences in context. A major line of evidence for sequence recall is the "phase precession" of hippocampal place cells. In the second part of the paper, we review the evidence for theta-gamma phase coding. According to a framework that incorporates this form of coding, the phase precession is interpreted as cued recall of a discrete sequence of items from long-term memory. The third part of the paper deals with the issue of how the hippocampus could learn memory sequences. We show that if multiple items can be active within a theta cycle through the action of a short-term "buffer," NMDA-dependent plasticity can lead to the learning of sequences presented at realistic item separation intervals. The evidence for such a buffer function is reviewed. An important underlying issue is whether the hippocampal circuitry is configured differently for learning and recall. We argue that there are indeed separate states for learning and recall, but that both involve theta oscillations, albeit in possibly different forms. This raises the question of how neuromodulatory input might switch the hippocampus between learning and recall states and more generally how different neuromodulatory inputs reconfigure the hippocampus for different functions. In the fifth part of this paper we review our studies of dopamine and dopamine/NMDA interactions in the control of synaptic function. Our results show that dopamine dramatically reduces the direct cortical input to CA1 (the perforant path input), while having little effect on the input from CA3. In order to interpret the functional consequences of this pathway-specific modulation, it is necessary to understand the function of CA1 and the role of dopaminergic input from the ventral tegmental area (VTA). In the sixth part of this paper we consider several possibilities and address the issue of how dopamine hyperfunction or NMDA hypofunction, abnormalities that may underlie schizophrenia, might lead to the symptoms of the disease. Relevant to this issue is the demonstrated role of the hippocampus in novelty detection, a function that is likely to depend on sequence recall by the hippocampus. Novelty signals are generated when reality does not match the expectations generated by sequence recall. One possible site for computing mismatch is CA1, since it receives predictions from CA3 and sensory "reality" via the perforant path. Our data suggest that disruption of this comparison would be expected under conditions of dopamine hyperfunction or NMDA hypofunction. Also relevant is the fact that the VTA, which fires in response to novelty, may both depend on hippocampal-dependent novelty detection processes and, in turn, affect hippocampal function. Through large-scale modeling that considers both the processes performed by the hippocampus and the neuromodulatory loops in which the hippocampus is embedded, it is becoming possible to generate working hypotheses that relate synaptic function and malfunction to behavior.
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PMID:Storage, recall, and novelty detection of sequences by the hippocampus: elaborating on the SOCRATIC model to account for normal and aberrant effects of dopamine. 1173 8

Sigma receptors have recently been the target of drug development related to psychiatric disorders, including schizophrenia and depression, as well as cognitive enhancers. This paper focused on the sigma-receptor-mediated modulation of neuronal activity, especially the effects on aminergic neuron and hippocampal neuron activity. Dopaminergic neuron activities in the substantia nigra and ventral tegmental area (VTA) are variously modified by the systemic administration of sigma ligands. When applied with microiontophoresis, they are reported to increase dopaminergic neuron activity in the VTA. This activity may be involved in the psychotropic or antipsychotic effects of these ligands. Moreover, serotonergic neurons in the raphe nucleus and noradrenergic neurons in the locus coeruleus were activated by sigma ligands. These effects are probably related to the antidepressant activity of sigma receptor ligands. In the hippocampus, sigma ligands suppressed CA1 neuronal activity in vitro. The effects were suggested to be due to an increase in the threshold of action potential and decreased synaptic transmission efficacy. NMDA receptor function was modified in biphasic fashion related to doses of sigma ligands, that is, a lower dose facilitated the NMDA receptor functions, and a higher dose inhibited them. These effects on the hippocampal neurons may contribute to their neuroprotective and antiamnesic actions. Further studies are needed to elucidate the relation between the physiological function of sigma receptor and psychiatric diseases by the use of sigma receptor ligands and molecular techniques.
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PMID:[Modulation of neuronal activities in the central nervous system via sigma receptors]. 1191 6

Reelin is a glycoprotein ( approximately 400 kDa) secreted by GABAergic neurons into the extracellular matrix of the neocortex and hippocampus as well as other areas of adult rodent and nonhuman primate brains. Recent findings indicate that the heterozygote reeler mouse (haploinsufficient for the reeler gene) shares several neurochemical and behavioral abnormalities with schizophrenia and bipolar disorder with mania. These include (1) a downregulation of both reelin mRNA and the translated proteins, (2) a decrease in the number of dendritic spines in cortical and hippocampal neurons, (3) a concomitant increase in the packing density of cortical pyramidal neurons, and (4) an age-dependent decrease in prepulse inhibition of startle. Interestingly, the heterozygous reeler mouse does not exhibit the unstable gait or the neuroanatomy characteristic of the null mutant reeler mouse. Immunocytochemical studies of the expression of reelin in mice have been primarily limited to light microscopy. In this study we present new immunoelectron microscopy data that delineates the subcellular localization of reelin in the cortex and hippocampus of the wild-type mouse, and compares these results to reelin expression in the heterozygous reeler mouse. In discontinuous areas of cortical layers I and II and the inner blade area of the dentate gyrus of the wild type mouse, extracellular reelin is associated with dendrites and dendritic spine postsynaptic specializations. Similar associations have been detected in the CA1 stratum oriens and other areas of the hippocampus. In the hippocampus, reelin expression is more expansive and more widespread than in cortical layers I and II. In contrast, extracellular reelin immunoreactivity is greatly diminished in all areas examined in the heterozygous reeler mouse. However, some cell bodies of GABAergic neurons in the cortex and hippocampus demonstrate an increased accumulation of reelin in the Golgi and endoplasmic reticulum. We suggest that in the heterozygous reeler mouse a downregulation of reelin biosynthesis results in a decreased rate of secretion into the extracellular space. This inhibits dendritic spine maturation and plasticity and leads to dissociation of dendritic postsynaptic density integrity and atrophy of spines. We speculate that the haploinsufficient reeler mouse may provide a model for future studies of the role of reelin, as it may be related to psychosis vulnerability.
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PMID:Reelin in the extracellular matrix and dendritic spines of the cortex and hippocampus: a comparison between wild type and heterozygous reeler mice by immunoelectron microscopy. 1195 Oct 52

The finding of pyramidal cell disarray in the hippocampus of patients with schizophrenia has been disputed by several groups. Conflicting results have been attributed to differences in the subtype of patients used, staining method, the side of the hippocampus studied and the way cellular disarray has been measured. In the present study, we correct for these confounds by using a well-defined population of schizophrenic patients (n = 14) and controls (n = 10) in which Golgi impregnated material was available. Measurements were performed manually according to the method of Kovelman and Scheibel (1984). Pyramidal cell disarray for the CA1/prosubicular interface indicated significant differences between patients and controls (p = 0.0183). The findings were attributed to a bias accrued to referencing measurements in schizophrenics to the distorted circumventricular surface of the temporal horn.
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PMID:Shape distortion of the hippocampus: a possible explanation of the pyramidal cell disarray reported in schizophrenia. 1195 60

The objective of the present study was to examine whether neurofibrillary tangles densities are increased in elderly patients with late-onset schizophrenia (LOS). A neuropathological examination was performed in 32 consecutive autopsy brain specimens of ten patients with early-onset schizophrenia (EOS; onset of symptoms before the age of 40 years), eight patients with LOS (onset of symptoms after the age of 40 years) and 14 age-matched controls with no known neuropsychiatric disorder. Neurofibrillary tangle densities observed in the CA1 field of the hippocampus, the enthorhinal cortex, and the inferior temporal cortex in patients with LOS, EOS, and controls were not significantly different. All patients with EOS or LOS had Braak stages of III or less, which may correspond to normal aging. Thus, patients with schizophrenia, regardless of the age of onset of their symptoms, are no more prone to the development of Alzheimer's disease than the general population.
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PMID:Neurofibrillary tangles in elderly patients with late onset schizophrenia. 1198 39


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