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)

Calcium-binding proteins (CBPs) such as calbindin, parvalbumin and calretinin are used as immunohistochemical markers for discrete neuronal subpopulations. They are particularly useful in identifying the various subpopulations of GABAergic interneurons that control output from prefrontal and cingulate cortices as well as from the hippocampus. The strategic role these interneurons play in regulating output from these three crucial brain regions has made them a focus for neuropathological investigation in schizophrenia. The number of pathological reports detailing subtle changes in these CBP-containing interneurons in patients with schizophrenia is rapidly growing. These proteins however are more than convenient neuronal markers. They confer survival advantages to neurons and can increase the neuron's ability to sustain firing. These properties may be important in the subtle pathophysiology of nondegenerative phenomena such as schizophrenia. The aim of this review is to introduce the reader to the functional properties of CBPs and to examine the emerging literature reporting alterations in these proteins in schizophrenia as well as draw some conclusions about the significance of these findings.
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PMID:Neuronal calcium-binding proteins and schizophrenia. 1216 73

Markers of inhibitory neurotransmission are altered in the prefrontal cortex (PFC) of subjects with schizophrenia, and several lines of evidence suggest that these alterations may be most prominent in the subset of GABA-containing neurons that express the calcium-binding protein, parvalbumin (PV). To test this hypothesis, we evaluated the expression of mRNAs for PV, another calcium-binding protein, calretinin (CR), and glutamic acid decarboxylase (GAD67) in postmortem brain specimens from 15 pairs of subjects with schizophrenia and matched control subjects using single- and dual-label in situ hybridization. Signal intensity for PV mRNA expression in PFC area 9 was significantly decreased in the subjects with schizophrenia, predominantly in layers III and IV. Analysis at the cellular level revealed that this decrease was attributable principally to a reduction in PV mRNA expression per neuron rather than by a decreased density of PV mRNA-positive neurons. In contrast, the same measures of CR mRNA expression were not altered in schizophrenia. These findings were confirmed by findings from cDNA microarray studies using different probes. Across the subjects with schizophrenia, the decrease in neuronal PV mRNA expression was highly associated (r = 0.84) with the decrease in the density of neurons containing detectable levels of GAD67 mRNA. Furthermore, simultaneous detection of PV and GAD67 mRNAs revealed that in subjects with schizophrenia only 55% of PV mRNA-positive neurons had detectable levels of GAD67 mRNA. Given the critical role that PV-containing GABA neurons appear to play in regulating the cognitive functions mediated by the PFC, the selective alterations in gene expression in these neurons may contribute to the cognitive deficits characteristic of schizophrenia.
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PMID:Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. 1286 16

Increased neuronal density, cortical thinning, and alterations of GABAergic interneurons in the prefrontal cortex have been associated with the pathophysiology of schizophrenia. This study used antibodies directed against the calcium-binding proteins, calretinin (CR), parvalbumin (PV), and calbindin (CB) to compare the relative density of subpopulations of GABAergic interneurons in BA9 of the prefrontal cortex from six subjects with schizophrenia and six control subjects matched for age, gender, and postmortem interval. The relative density of interneurons expressing CR, PV, or CB did not differ significantly between subjects with schizophrenia and control subjects. In addition, no change in somal size of immunoreactive (IR) neurons or cortical thickness was observed between the two groups. This study supports previous reports consistently demonstrating no change in the relative density of interneurons expressing CR in the dorsolateral prefrontal cortex in schizophrenia but does not support previous inconsistent findings that the relative density of interneurons expressing PV and CB might be altered in this disorder.
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PMID:Neurons expressing calcium-binding proteins in the prefrontal cortex in schizophrenia. 1475 22

As quantitative neuroimaging continues to elucidate the gross neuropathology of schizophrenia, neurochemical and histological studies have contributed to defining this pathology in terms of neurotransmitter dysfunction. Increasingly, there is evidence implicating neurons containing the major inhibitory neurotransmitter of the brain--gamma-aminobutyric acid (GABA). Benes was the first to demonstrate deficits in some morphological subtypes of interneurons in the frontal cortex in schizophrenia. We identified that this was specific to a subgroup of GABAergic interneurons containing parvalbumin (PV), which is found in the fast-firing cells providing inhibitory control of the cortico-fugal pyramidal cells. PV is notable in being expressed late in development; the late expression of this protective calcium binding protein (CBP) may impart an early vulnerability to these neurons, indicating a possible mechanism for the developmental origins of schizophrenia. Cortical GABAergic neurons expressing the CBP calretinin (CR) are unaffected in schizophrenia, although those containing calbindin (CB) are also diminished in number. These deficits in PV and CB are notable in also being observed in bipolar disorder, indicating how the close aetiological relationship of these two psychiatric disorders is reflected in their pathology. One of the most substantial abnormalities seen in post-mortem brain tissue is the hippocampal deficit of PV-containing neurons, again in the absence of effects on CR-positive cells. This deficit occurring in a structure implicated in cognitive symptomatology may well have functional relevance, and we find it can be induced by a model of the disease, sub-chronic phencyclidine (PCP) administration, that can also produce cognitive disturbances. This PCP model, like schizophrenia, demonstrates other neurochemical changes which include indicators of glutamatergic dysfunction. The temporal and aetiological relationships between glutamatergic and GABAergic deficits remains unclear, but may well relate to an initial loss/dysfunction of GABA/PV neurons that subsequently gives rise to a glutamatergic pathology.
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PMID:Calcium binding protein markers of GABA deficits in schizophrenia--postmortem studies and animal models. 1518 6

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

GABAergic neuronal subpopulations, defined by the presence of the calcium binding proteins, parvalbumin (PV) and calretinin (CR) are differentially affected in schizophrenia, with selective PV deficits reported in the prefrontal cortex and hippocampus. To assess the possible contribution of antipsychotic treatment to these effects we examined the size and density of PV-and CR-IR neurons in the rat frontal cortex and hippocampus following three weeks of chronic haloperidol or clozapine administration. Neither antipsychotic significantly altered PV- or CR-IR neuronal cell parameters in these areas or in any of their subregions, relative to controls. These results suggest antipsychotic exposure does not contribute to PV-IR neuronal deficits in schizophrenic patients, providing further evidence in support of a developmental abnormality in specific subpopulations of GABAergic neurons in schizophrenia.
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PMID:Chronic haloperidol or clozapine treatment does not alter parvalbumin immunoreactivity in the rat frontal cortex or hippocampus. 1555 77

Treatment of rats with methylazoxymethanol (MAM) on gestational day (GD)17 disrupts corticolimbic development in the offspring (MAM-GD17 rats) and leads to abnormalities in adult MAM-GD17 rats resembling those described in schizophrenic patients. The underlying changes in specific cortical and limbic cell populations remain to be characterised. In schizophrenia, decreases in inhibitory gamma-aminobutyric acid (GABA)-containing interneurons that express the calcium-binding protein parvalbumin have been reported in the prefrontal cortex and hippocampus. In this study we analysed the expression of parvalbumin (PV), calretinin (CR) and calbindin (CB) in the prefrontal cortex and hippocampus of MAM-GD17 rats. Exposure in utero to MAM led to a significant decrease in the number of neurons expressing PV in the hippocampus, but not the prefrontal cortex. Neurons expressing CR or CB were not affected in either structure. The neurochemical changes in MAM-GD17 rats were accompagnied by increased hyperlocomotion after administration of phencyclidine (PCP), analogous to the hypersensitivity of schizophrenic patients to PCP. Therefore, the developmental MAM-GD17 model reproduces key neurochemical and behavioural features that reflect cortical and subcortical dysfunction in schizophrenia, and could be a useful tool in the development of new antipsychotic drugs.
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PMID:Decrease in parvalbumin-expressing neurons in the hippocampus and increased phencyclidine-induced locomotor activity in the rat methylazoxymethanol (MAM) model of schizophrenia. 1642 Apr 37

A series of studies in schizophrenic patients report a decrease of glutathione (GSH) in prefrontal cortex (PFC) and cerebrospinal fluid, a decrease in mRNA levels for two GSH synthesizing enzymes and a deficit in parvalbumin (PV) expression in a subclass of GABA neurons in PFC. GSH is an important redox regulator, and its deficit could be responsible for cortical anomalies, particularly in regions rich in dopamine innervation. We tested in an animal model if redox imbalance (GSH deficit and excess extracellular dopamine) during postnatal development would affect PV-expressing neurons. Three populations of interneurons immunolabeled for calcium-binding proteins were analyzed quantitatively in 16-day-old rat brain sections. Treated rats showed specific reduction in parvalbumin immunoreactivity in the anterior cingulate cortex, but not for calbindin and calretinin. These results provide experimental evidence for the critical role of redox regulation in cortical development and validate this animal model used in schizophrenia research.
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PMID:Glutathione deficit during development induces anomalies in the rat anterior cingulate GABAergic neurons: Relevance to schizophrenia. 1648 Nov 79

Psychiatric illnesses, particularly schizophrenia, are associated with disrupted markers for interneuronal function and interneuron-mediated brain rhythms such as gamma frequency oscillations. Here we investigate a possible link between these two observations in the entorhinal cortex and hippocampus by using a genetic and an acute model of psychiatric illness. Lysophosphatidic acid 1 receptor-deficient (LPA1-deficient) mice show psychomotor-gating deficits and neurochemical changes resembling those seen in postmortem schizophrenia studies. Similar deficits are seen acutely with antagonism of the NMDA subtype of glutamate receptor. Neither model induced any change in power or frequency of gamma rhythms generated by kainate in hippocampal slices. In contrast, a dramatic decrease in the power of gamma oscillations was seen in superficial, but not deep, medial entorhinal cortex layers in both models. Immunolabeling for GABA, parvalbumin, and calretinin in medial entorhinal cortex from LPA1-deficient mice showed an approximately 40% reduction in total GABA- and parvalbumin-containing neurons, but no change in the number of calretinin-positive neurons. This deficit was specific for layer II (LII). No change in the number of neurons positive for these markers was seen in the hippocampus. Acute NMDA receptor blockade, which selectively reduces synaptic drive to LII entorhinal interneurons, also disrupted gamma rhythms in a similar manner in superficial entorhinal cortex, but not in hippocampus. These data demonstrate an area-specific deficit in gamma rhythmogenesis in animal models of psychiatric illness and suggest that loss, or reduction in function, of interneurons having a large NMDA receptor expression may underlie the network dysfunction that is seen.
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PMID:Region-specific reduction in entorhinal gamma oscillations and parvalbumin-immunoreactive neurons in animal models of psychiatric illness. 1652 56

Despite a delayed emergence of the symptoms, schizophrenia is thought to be a late consequence of early disturbances during development. Several reports have found decreased levels of reelin in the cortex and the hippocampus of postmortem brains of schizophrenic patients. In the rat, intraperitoneal injection of the anti-mitotic agent methylazoxymethanol (MAM) during intra-uterine development (embryonic day 17) induces cytoarchitectural abnormalities in the hippocampus and the cortex and behavioural changes reminiscent of positive, negative and cognitive symptoms of schizophrenia. We aimed to examine whether a transient prenatal disturbance of neurogenesis induces postnatal changes in the expression of reelin in the hippocampus. Cellular modifications were explored using hippocampal organotypic slice cultures, which allow for conservation of the in vivo cytoarchitecture. MAM effect on hippocampal neurogenesis was confirmed by birthdating experiments. After 3 weeks in vitro, reelin was expressed by calretinin-negative cells. The number of reelin-positive neurons was increased whereas the total neuron number was decreased in the stratum oriens in the E17 MAM-exposed animals as compared to the control group. Not only an increase in the number of cells expressing reelin was observed, but there was also a slight increase in reelin mRNA levels in hippocampal pyramidal cells of MAM-exposed animals. In contrast, there was no significant change in the dentate gyrus. These results show that transient prenatal disturbance of neurogenesis induces long-term modifications in specific areas of the hippocampus and in particular in the number of neurons expressing reelin. They also confirm the value of organotypic slices to study postnatal maturation in the hippocampus.
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PMID:Postnatal effect of embryonic neurogenesis disturbance on reelin level in organotypic cultures of rat hippocampus. 1673 48


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