Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies on the molecular basis of neurological and psychiatric disorders often rely on the precise determination of specific proteins in brain tissues. In this study, we have developed a method for measuring the levels of the neural-specific growth-associated protein, GAP-43, in human postmortem brain specimens. This rapid and quantitative method is based on immunodetection procedures. Briefly, synaptosomal plasma membranes (SPMs) are deposited onto polyvinylidene difluoride (PVDF) membranes via a dot-blotting apparatus, followed by specific GAP-43 detection using a monospecific polyclonal antibody. Overall, the dot-blot procedure provided several advantages over Western blots and one-dimensional and two-dimensional polyacrylamide gels. The assays were more sensitive, reproducible, and allowed the rapid and simultaneous determination of multiple samples. Using this technique, we examined the levels of the GAP-43 protein in Brodmann's areas 17, 20, and 10 of schizophrenic and age-, sex-, and postmortem interval (PMI) matched controls. These studies revealed an increase in the levels of GAP-43 in visual association and frontal cortices (areas 20 and 10) of schizophrenic brains. Given the relationship of GAP-43 expression with the establishment and remodeling of neural connections, our results support the hypothesis that schizophrenia is associated with a perturbed organization of synaptic connections in associative areas of the human brain.
 ...
PMID:Increased levels of GAP-43 protein in schizophrenic brain tissues demonstrated by a novel immunodetection method. 775 43

The pathophysiology of schizophrenia may involve perturbations of synaptic organization during development. The presence of cytoarchitectural abnormalities that may reflect such perturbations in the brains of patients with this disorder has been well-documented. Yet the mechanistic basis for these features of the disorder is still unknown. We hypothesized that altered regulation of the neuronal growth-associated protein GAP-43, a membrane phosphoprotein found at high levels in the developing brain, may play a role in the alterations in brain structure and function observed in schizophrenia. In the mature human brain, GAP-43 remains enriched primarily in association cortices and in the hippocampus, and it has been suggested that this protein marks circuits involved in the acquisition, processing, and/or storage of new information. Because these processes are known to be altered in schizophrenia, we proposed that GAP-43 levels might be altered in this disorder. Quantitative immunoblots revealed that the expression of GAP-43 is increased preferentially in the visual association and frontal cortices of schizophrenic patients, and that these changes are not present in other neuropsychiatric conditions requiring similar treatments. Examination of the levels of additional markers in the brain revealed that the levels of the synaptic vesicle protein synaptophysin are reduced in the same areas, but that the abundance of the astrocytic marker of neurodegeneration, the glial fibrillary acidic protein, is unchanged. In situ hybridization histochemistry was used to show that the laminar pattern of GAP-43 expression appears unaltered in schizophrenia. We propose that schizophrenia is associated with a perturbed organization of synaptic connections in distinct cortical associative areas of the human brain, and that increased levels of GAP-43 are one manifestation of this dysfunctional organization.
 ...
PMID:Levels of the growth-associated protein GAP-43 are selectively increased in association cortices in schizophrenia. 894 81

Studies in the past have revealed serotonin to play a role in regulating the development and maturation of the mammalian brain, largely through the release of the astroglial protein S-100beta. S-100beta plays a role in neurite extension, microtubule and dendritic stabilization and regulation of the growth associated protein GAP-43, all of which are key elements in the production of synapses. Depletion of serotonin, and thus of S-100beta, during synaptogenesis should lead to a loss of synapses and the behaviors dependent on those synapses. The current study was undertaken to test this hypothesis. In order to assess the influence of serotonin we have looked at the synaptic density in the adult after depletion, by using immunodensitometry of synaptic markers (synaptophysin and MAP-2) and by studying behaviors thought to be highly dependent on synaptic plasticity and density. Male Sprague-Dawley rats were depleted of serotonin on postnatal days (PND) 10-20 by treating with the tryptophan hydroxylase inhibitor parachlorophenylalanine (PCPA; 100 mg/kg, s.c.). On PND's 30 and 62, animals were perfused for immunodensitometry. Littermates were used for behavioral testing. At PND 55-62, the animals were tested in an interchangeable maze with olfactory cues and in an eight-arm radial maze. Our results show a loss of both synaptic markers in the hippocampus on PND 30. At PND 62, the only remaining loss was of the dendritic marker MAP-2. The animals had deficits in both behaviors tested, suggestive of spacial learning deficits and of the failure to extinguish learned behaviors or to re-learn in a new set. Our findings show the long-term consequences of interfering with the role of serotonin in brain development on the morphology and function of the adult brain. These findings may have implications for human diseases, including schizophrenia, thought to be related to neurodevelopmental insults such as malnutrition, hypoxia, viruses or in utero drug exposure. Moreover, they provide further insights into the functioning of serotonin and S-100beta in development and aging.
 ...
PMID:Serotonin depletion during synaptogenesis leads to decreased synaptic density and learning deficits in the adult rat: a possible model of neurodevelopmental disorders with cognitive deficits. 923 19

The hippocampal formation (HF) has been a centerpiece of neuropathologic investigations of schizophrenia. Numerous MRI studies have demonstrated a slight bilateral reduction in HF volume. Reports of reduced N-acetyl aspartate measured with in vivo proton spectroscopy suggest that neuronal pathology exists. However, morphometric data from postmortem studies have not revealed a clear change in HF size, and recent studies of neuronal number and of cytoarchitecture have been largely negative. Evidence of glial proliferation is consistently absent. The most reproducible positive anatomic finding in postmortem HF has been reduced size of neuronal cell bodies. Studies of gene transcription have provided replicable evidence of decreased expression of mRNAs for synaptophysin, GAP-43, cholecystokinin, and non-NMDA glutamate receptor subunits (GLU R 1 and 2), particularly in CA 3-4. These data about the cellular and molecular biology of the HF in schizophrenia are different from that found in a number of conditions associated with hippocampal damage, including excitotoxicity, epilepsy, alcoholism, Alzheimer's disease, steroid neurotoxicity, and normal aging. Notwithstanding the real possibility that the data are epiphenomena of chronic illness, the findings may implicate a unique cellular defect in schizophrenia--a genetic variation affecting the plasticity of HF circuitry and connectivity. Directions for further research are proposed.
 ...
PMID:Cell biology of the hippocampal formation in schizophrenia. 1007 7

Synaptic pathology is central in the pathogenesis of several psychiatric disorders, for example in Alzheimer's disease (AD) and schizophrenia. Quantification of specific synaptic proteins has proved to be a useful method to estimate synapitc density in the brain. Using this approach, several synaptic proteins have been demonstrated to be altered in both AD and schizophrenia. Until recently, the analysis of synaptic pathology has been limited to postmortem tissue. In living subjects, these synaptic proteins may be studied through analysis of cerebrospinal fluid (CSF). In an earlier study performed by us, one synaptic vesicle specific protein, synaptotagmin, was detected in CSF for the first time using a procedure based on affinity chromatography, reversed-phase chromatography, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and chemiluminescence immunoblotting. However, other synaptic proteins were not detectable with this procedure. Therefore, we have developed a procedure including precipitation of CSF proteins with trichloroacetic acid, followed by liquid-phase isoelectric focusing using the Rotofor Cell, and finally analysis of Rotofor fractions by Western blotting for identification of synaptic proteins in CSF. Five synaptic proteins, rab3a, synaptotagmin, growth-associated protein (GAP-43), synaptosomal-associated protein (SNAP-25) and neurogranin, have been demonstrated in CSF using this method. The major advantage of liquid-phase isoelectric focusing (IEF) using the Rotofor cell is that it provides synaptic proteins from CSF in sufficient quantities for identification. This method may also be suitable for identification of other types of trace amounts of brain-specific proteins in CSF. These results demonstrate that several synaptic proteins can be identified and measured in CSF to study synaptic function and pathology in degenerative disorders.
 ...
PMID:Identification of synaptic vesicle, pre- and postsynaptic proteins in human cerebrospinal fluid using liquid-phase isoelectric focusing. 1021 48

Behavioral sensitization or reverse tolerance induced by repeated treatment of psychostimulants, such as amphetamine and cocaine, has been widely used as an animal model for schizophrenia. This phenomenon may result from almost eternally lasting plastic functional adaptation in the brain. Such long-lasting plasticity must accompany anatomical and morphological neural changes. Histological studies revealed that chronic treatment of psychostimulants induced thickness, elongation and an increased branch number of neurites and dendrites in cortices and accumbens, and an increased spine density. These changes may seem a positive adaptation for neural transmission, however, similar histological changes were seen after toxicity of methamphetamine as deafferation compensation. Therefore, further studies are needed to establish the significance of these morphological changes induced by chronic psychostimulants. On the other hand, neuromolecular studies showed increased phosphorylation of neuromodulin, increased expression of tissue-type plasminogen activator, synaptotagmin IV and arc, which are assumed to play roles in neural outgrowth and synaptogenesis. Although all of these histological and neuromolecular findings may suggest reorganization of the neural network should grow along with behavioral sensitization, more solid evidence is indispensable to confirm it.
 ...
PMID:[Is there solid evidence for reorganization of the neural network associated with development of behavioral sensitization to psychostimulants?]. 1046 75

Schizophrenia has been associated with anatomical and functional abnormalities of the dorsolateral prefrontal cortex (DLPFC), which may reflect abnormal connections of DLPFC neurons. We measured mRNA levels of growth-associated protein (GAP-43), a peptide linked to the modifiability of neuronal connections, in post-mortem brain tissue from two cohorts of patients with schizophrenia and controls. Using the RNase protection assay (RPA), we found a significant reduction in GAP-43 mRNA in the DLPFC, but not in the hippocampus, of patients with schizophrenia. With in situ hybridization histo- chemistry (ISHH), performed on a separate cohort, we confirmed the reduction of GAP-43 mRNA in the DLPFC of patients with schizophrenia. We detected reduced GAP-43 mRNA per neuron in layers III, V and VI of patients with schizophrenia compared with normal controls and patients with bipolar disorder. Thus, glutamate neurons in DLPFC of schizophrenic patients may synthesize less GAP-43, which could reflect fewer and/or less modifiable connections than those in normal human brain, and which may be consistent with the deficits of prefrontal cortical function that characterize schizophrenia.
 ...
PMID:Reduced GAP-43 mRNA in dorsolateral prefrontal cortex of patients with schizophrenia. 1120 68

The discovery of lithium's efficacy as a mood-stabilizing agent revolutionized the treatment of patients with bipolar disorder and after 5 decades this drug continues to be the mainstay of treatment of this disorder. Valproate, which is dissimilar structurally to lithium, shares most of the effects of lithium at the level of protein kinase C (PKC). Both drugs reduce the activity of PKC, though via different mechanisms. In comparison to patients with major depressive disorder, schizophrenia, or healthy controls, PKC activity is significantly elevated in manic patients, suggesting that changes of PKC activity may be a central pathological trait of the illness. The precise physiological role of PKC activity in the regulation of mood is unclear. The enzyme modulates cellular responses via phosphorylation of numerous substrate proteins. Such substrates of PKC include cytoskeletal proteins, neurotransmitter and hormone receptors, G proteins, GAP-43, MARCKS etc. Further studies are required to clarify any causal role of CPK changes in bipolar-disorder.
 ...
PMID:[On the relevance of protein kinase C to lithium therapy in bipolar disorder]. 1552 99

Growth-associated protein 43 (GAP-43) expression is critical for the proper establishment of neural circuitry, a process thought to be disrupted in schizophrenia. Previous work from our laboratory demonstrated decreased GAP-43 levels in post-mortem tissue from the entire hippocampal formation of affected individuals. In the present study, we used immunocytochemical techniques to localize alterations in GAP-43 protein to specific synapses. GAP-43 distribution was compared to that of synaptophysin, another synaptic protein known to be altered in schizophrenia. The levels and distribution of GAP-43 and synaptophysin proteins were measured in the dentate gyrus of subjects with schizophrenia and sex-, age-, and postmortem interval-matched normal controls and subjects with bipolar disorder. Tissue from subjects was provided by the Harvard Brain Tissue Resource Center. In control subjects, GAP-43 immunostaining was prominent in synaptic terminals in the inner molecular layer and hilar region. Subjects with schizophrenia had significant decreases in GAP-43 immunoreactivity in the hilus (p<0.05, paired t-test) and inner molecular layer (p<0.05, paired t-test) but not in the outer molecular layer. In the same tissues, synaptophysin immunoreactivity was significantly reduced in both the inner and outer molecular layers of the dentate gyrus (both p<0.01 by paired t-test), but not in the hilus. In contrast to patients with schizophrenia, GAP-43 and synaptophysin levels in subjects with bipolar disorder did not differ from controls. Given the relationship of GAP-43 and synaptophysin with the development and plasticity of synaptic connections, the observed alterations in the hippocampus of patients with schizophrenia may be related to cognitive deficits associated with this illness.
 ...
PMID:Growth-associated protein 43 (GAP-43) and synaptophysin alterations in the dentate gyrus of patients with schizophrenia. 1569 36

Impairment of neuroplasticity is considered to play a role in the pathogenesis of psychiatric disorders. To further characterize the impairment of neuroplasticity in psychiatric disorders, expression of the neuronal plasticity marker 43 kDa growth-associated protein (GAP-43) was detected in postmortem hippocampal sub-regions from psychiatric patients including major depressive disorder, bipolar disorder and schizophrenia subjects, and matched control subjects. We found that GAP-43 protein levels in the hippocampal hilar region were significantly lower in bipolar disorder and schizophrenia subjects than in control subjects. We also found that GAP-43 protein levels in the inner molecular layer of the dentate gyrus and the stratum radiatum of CA2 region were reduced in a trend in bipolar disorder and schizophrenia subjects when compared with control subjects. These results suggest that impairment of neuroplasticity may occur in the hippocampus of bipolar disorder and schizophrenia patients.
 ...
PMID:Immunoreactivity of 43 kDa growth-associated protein is decreased in post mortem hippocampus of bipolar disorder and schizophrenia. 1709 55


1 2 Next >>