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

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

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

Chandelier neurons and their characteristic arrays of axonal terminals, known as cartridges, have been implicated in a variety of psychiatric and neurological disorders including schizophrenia and epilepsy. As a result, these neurons have been extensively examined in the brains of several species using a range of markers. However, these markers have not been systematically compared in a single species for their robustness in labelling chandelier cell cartridges. We have therefore examined several markers, reported to label chandelier arrays in primates, for their capacity to mark these structures in rat medial prefrontal cortex and hippocampus. These studies revealed that cartridge-like structures were labelled by parvalbumin and GAT-1 immunohistochemistry in both medial prefrontal cortex and hippocampus of the rat brain. Additionally, GAD65 immunohistochemistry labelled array-like structures preferentially in the dentate gyrus. In contrast, PSA-NCAM, calbindin and GAD67 immunohistochemistry did not reveal any array-like structures in either region of rat brain. These observations indicate that the various immunological markers previously used to visualise chandelier cell cartridges in primates are not equally efficient in labelling these structures in the rat brain, and that GAT-1 immunohistochemistry is the most robust means of visualising chandelier cell cartridges in the regions examined. These are important considerations for quantitative studies in animal models of neurological disorders where chandelier neurons are implicated.
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PMID:A comparison of possible markers for chandelier cartridges in rat medial prefrontal cortex and hippocampus. 1564 49

Reduced density of calbindin-containing interneurons in the prefrontal cortex in schizophrenia has been reported (Beasley et al 2002; Biol Psych 52:708-715). Calbindin is a calcium-binding protein (CBP) present in a subpopulation of GABAergic neurons restricted mainly to layer II of the cortex. A paraffin-embedded, 10-mum-thick section from the planum temporale (PT) of each hemisphere was prepared from 12 patients with schizophrenia and 12 controls. Calbindin-containing cells were stained using an antibody (D-28K). Counting frames were superimposed to sample within layer II of the PT. A bilateral reduction (20%) in calbindin cell density was found in patients (controlling for fixation time). Furthermore, mean calbindin cell cross-sectional area was increased in female patients and reduced in male patients. Reduced CBP expression (reducing the excitability of interneurons) or reduced number of CBP-containing cells may cause disinhibition of pyramidal cells. The majority of calbindin-containing cells in the mature brain are double-bouquet cells with vertically oriented dendrites and axon bundles. By exercising inhibitory modulation of pyramidal cells in a columnar arrangement, they make possible cohesive vertical inhibition of minicolumns. Loss of columnar inhibition may result in reduced minicolumnar segregation and altered cell size may reflect altered minicolumn size.
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PMID:Reduced density of calbindin-immunoreactive interneurons in the planum temporale in schizophrenia. 1592 48

Olfactory deficits, observed in schizophrenia, may be associated with a disruption of synaptic transmission in the olfactory system. Using immunohistochemistry and optical densitometry, we assessed the integrity of the synaptic connection between olfactory receptor neurons and olfactory bulb target neurons in schizophrenia by comparing the level of eight proteins, expressed in the olfactory bulb glomeruli, among schizophrenia and control subjects. In schizophrenia, no change was observed in the levels of OMP, GAP43 and NCAM, proteins expressed by olfactory receptor neurons, suggesting an intact innervation of the olfactory bulb by these neurons. This was supported by the absence of change in calbindin level, which has been shown to decrease after the destruction of the olfactory epithelium. The level of synaptophysin, a pre-synaptic protein, was also unchanged. These findings suggested that axons of olfactory receptor neurons establish synapses with their olfactory bulb targets in schizophrenia. The absence of change in the level of poorly phosphorylated neurofilament of moderate and high molecular weight (NFM/HP) suggested no lack of dendritic innervation despite a previously seen reduction of glomerular MAP2 level in schizophrenia subjects. This and above findings were consistent with the absence of change in the level of beta-tubulin III, a protein expressed by neurons of both olfactory epithelium and bulb. Finally, we noted no significant decrease in trkB level, a neurotrophin receptor involved in the olfactory epithelium maintenance. This study showed no evidence of major structural alteration of the synapse between the olfactory epithelium and bulb in schizophrenia.
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PMID:Characterization of olfactory bulb glomeruli in schizophrenia. 1594 25

The striatum processes motor, cognitive, and limbic circuitry. Striatal patch and matrix compartments are organized differently in many aspects including connectivity. Abnormalities in either compartment could have different functional consequences. The present study compares the synaptic organization in the patches and matrix in subjects with schizophrenia (SZ, n = 14) versus normal controls (NC, n = 8). Postmortem striatal tissue was processed for calbindin immunocytochemistry to identify the patch versus matrix compartments, prepared for electron microscopy, and analyzed using stereology. Several synaptic changes were observed in the SZ subjects vs. NCs including a higher density of cortical-type synapses in the putamen patch (44% higher) and in the caudate matrix (36% higher) in SZ cases on typical antipsychotic drugs. These changes appeared to be normalized rather than caused by treatment. The abnormal connectivity may represent a failure of normal synaptic pruning and may play a role in limbic or cognitive dysfunction in schizophrenia.
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PMID:Synaptic differences in the patch matrix compartments of subjects with schizophrenia: a postmortem ultrastructural study of the striatum. 1624 39

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


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