| 1 | Anal. Quant. Cytol. Histol. 2000 Apr 22: 178-82 |
|---|---|
| PMID | 10800621 |
| Title | 3-D Golgi and image analysis of the olfactory tubercle in schizophrenia. |
| Abstract | To examine morphologic changes in the olfactory tubercle (OT) spiny neurons and astrocytes in schizophrenia (Sch) by means of quantitative 3-D Golgi and immunocytochemical studies. Free-floating vibrotome sections of postmortem brain tissue from 10 controls and 12 Sch cases were used for Golgi study and glial fibrillary acidic protein (GFAP) immunocytochemistry. A gray level image analysis was applied for quantitative estimation of GFAP-positive astrocytes on uniform, randomly sampled sections. This method is effective for low-contrast objects on an uneven background. Golgi-impregnated OT spiny neurons were analyzed both qualitatively and quantitatively in three dimensions with a semiautomated microscope-computer system. From digitized image of the neurons, various metric parameters were estimated to characterize the dendritic tree. In cases of Sch, degenerative changes in the dendrites of OT spiny neurons were revealed. A decrease in the maximal radius of the dendritic tree and total length of dendrites were accompanied by an increase in the length density of dendrites. Hypertrophy and a more-intensive GFAP reaction of astrocytes were found in OT of Sch. Based on these results, one can hypothesize that OT spiny neurons in Sch are involved in the process of dendritic reorganization, including degenerative changes in dendrites. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Brain Res. Bull. 2000 Apr 51: 499-505 |
| PMID | 10758340 |
| Title | Cellular localization of serotonin(2A) (5HT(2A)) receptors in the rat brain. |
| Abstract | The serotonin(2A) (5HT(2A)) receptors have been shown to play an important role in several psychiatric disorders, including depression, schizophrenia, and alcoholism. This immunohistochemical study examined the cellular localization of 5HT(2A) receptors in various rat brain structures (olfactory, striatum, cortex, hippocampus, and amygdala). The colocalization of 5HT(2A) receptors in astrocytes was performed by double-immunofluorescence staining of 5HT(2A) receptors and of glial fibrillary acidic protein (GFAP) using confocal laser microscopy. 5HT(2A) receptor immunolabeling was observed in olfactory bulbs, neostriatum, hippocampus, amygdala, and neocortex. Somata and dendrites of pyramidal cells in the frontal cortex (layer V) were densely labeled with 5HT(2A) receptors. In several other brain structures (hippocampus, amygdala, striatum, olfactory structures), 5HT(2A) receptor immunolabeling was found in cell bodies and processes of neurons. 5HT(2A) receptor immunolabeling was also observed in GFAP-positive cells of the various brain structures we investigated (layers I/VI of the neocortex, corpus callosum, hippocampal fissure and hilus, and amygdala). These results indicate that 5HT(2A) receptors are expressed in neurons and astrocytes and suggest the possibility that not only neuronal but also glial 5HT(2A) receptors have functional implications in psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Mol. Psychiatry 2000 Mar 5: 142-9 |
| PMID | 10822341 |
| Title | Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium. |
| Abstract | Severe psychiatric disorders such as schizophrenia, bipolar disorder and major depressive disorder are brain diseases of unknown origin. No biological marker has been documented at the pathological, cellular, or molecular level, suggesting that a number of complex but subtle changes underlie these illnesses. We have used proteomic technology to survey postmortem tissue to identify changes linked to the various diseases. Proteomics uses two-dimensional gel electrophoresis and mass spectrometric sequencing of proteins to allow the comparison of subsets of expressed proteins among a large number of samples. This form of analysis was combined with a multivariate statistical model to study changes in protein levels in 89 frontal cortices obtained postmortem from individuals with schizophrenia, bipolar disorder, major depressive disorder, and non-psychiatric controls. We identified eight protein species that display disease-specific alterations in level in the frontal cortex. Six show decreases compared with the non-psychiatric controls for one or more diseases. Four of these are forms of glial fibrillary acidic protein (GFAP), one is dihydropyrimidinase-related protein 2, and the sixth is ubiquinone cytochrome c reductase core protein 1. Two spots, carbonic anhydrase 1 and fructose biphosphate aldolase C, show increase in one or more diseases compared to controls. Proteomic analysis may identify novel pathogenic mechanisms of human neuropsychiatric diseases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | J. Neuropathol. Exp. Neurol. 2000 Feb 59: 137-50 |
| PMID | 10749103 |
| Title | Increase in HLA-DR immunoreactive microglia in frontal and temporal cortex of chronic schizophrenics. |
| Abstract | Glia play a major role in neuronal migration, synapse formation, and control of neurotransmission in the developing and mature nervous system. This study investigated whether chronic schizophrenia is associated with glial changes in 3 regions of the cerebral cortex: dorsolateral prefrontal cortex (Brodmann's area 9), the superior temporal gyrus (area 22), and the anterior cingulate gyrus (area 24). In a blind study, astroglia and microglia were identified immunocytochemically in frozen sections from postmortem schizophrenic and control brains. Astroglia and microglia were identified using antibodies to glial fibrillary acidic protein (GFAP) and class II human leucocyte antigen (HLA-DR) respectively. They were then quantified for each cortical layer. Significant differences were found in HLA-DR+ microglial numerical density in 2 of the areas. A 28% increase (p < 0.05) was found in area 9 in 8 schizophrenics (115 +/- 9 cells/mm2) compared with 10 controls (89 +/- 5 cells/mm2), when combining all cortical layers and both cerebral hemispheres. For area 22, there was a 57% increase (p < 0.01) in microglia in 7 schizophrenics (139 +/- 6 cells/mm2) compared with 10 controls (88 +/- 5 cells/mm2). In area 24 the same trend was evident, but the results did not reach significance. Microglial number was further analyzed for each cortical layer, which confirmed the overall pattern. For all areas, numerical density of astroglia showed no significant differences between schizophrenics and controls. Cortical thickness was measured in all areas and total neuronal numerical density was estimated for area 22. Again, no significant differences were found between schizophrenics and controls. This study demonstrates a specific increase in the numerical density of HLA-DR+ microglia in temporal and frontal cortex of chronic schizophrenics, not related to aging, which might be implicated in possible changes in cortical neuropil architecture in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | J. Neuropathol. Exp. Neurol. 2000 Feb 59: 137-50 |
| PMID | 10749103 |
| Title | Increase in HLA-DR immunoreactive microglia in frontal and temporal cortex of chronic schizophrenics. |
| Abstract | Glia play a major role in neuronal migration, synapse formation, and control of neurotransmission in the developing and mature nervous system. This study investigated whether chronic schizophrenia is associated with glial changes in 3 regions of the cerebral cortex: dorsolateral prefrontal cortex (Brodmann's area 9), the superior temporal gyrus (area 22), and the anterior cingulate gyrus (area 24). In a blind study, astroglia and microglia were identified immunocytochemically in frozen sections from postmortem schizophrenic and control brains. Astroglia and microglia were identified using antibodies to glial fibrillary acidic protein (GFAP) and class II human leucocyte antigen (HLA-DR) respectively. They were then quantified for each cortical layer. Significant differences were found in HLA-DR+ microglial numerical density in 2 of the areas. A 28% increase (p < 0.05) was found in area 9 in 8 schizophrenics (115 +/- 9 cells/mm2) compared with 10 controls (89 +/- 5 cells/mm2), when combining all cortical layers and both cerebral hemispheres. For area 22, there was a 57% increase (p < 0.01) in microglia in 7 schizophrenics (139 +/- 6 cells/mm2) compared with 10 controls (88 +/- 5 cells/mm2). In area 24 the same trend was evident, but the results did not reach significance. Microglial number was further analyzed for each cortical layer, which confirmed the overall pattern. For all areas, numerical density of astroglia showed no significant differences between schizophrenics and controls. Cortical thickness was measured in all areas and total neuronal numerical density was estimated for area 22. Again, no significant differences were found between schizophrenics and controls. This study demonstrates a specific increase in the numerical density of HLA-DR+ microglia in temporal and frontal cortex of chronic schizophrenics, not related to aging, which might be implicated in possible changes in cortical neuropil architecture in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | J. Neuropathol. Exp. Neurol. 2000 Feb 59: 137-50 |
| PMID | 10749103 |
| Title | Increase in HLA-DR immunoreactive microglia in frontal and temporal cortex of chronic schizophrenics. |
| Abstract | Glia play a major role in neuronal migration, synapse formation, and control of neurotransmission in the developing and mature nervous system. This study investigated whether chronic schizophrenia is associated with glial changes in 3 regions of the cerebral cortex: dorsolateral prefrontal cortex (Brodmann's area 9), the superior temporal gyrus (area 22), and the anterior cingulate gyrus (area 24). In a blind study, astroglia and microglia were identified immunocytochemically in frozen sections from postmortem schizophrenic and control brains. Astroglia and microglia were identified using antibodies to glial fibrillary acidic protein (GFAP) and class II human leucocyte antigen (HLA-DR) respectively. They were then quantified for each cortical layer. Significant differences were found in HLA-DR+ microglial numerical density in 2 of the areas. A 28% increase (p < 0.05) was found in area 9 in 8 schizophrenics (115 +/- 9 cells/mm2) compared with 10 controls (89 +/- 5 cells/mm2), when combining all cortical layers and both cerebral hemispheres. For area 22, there was a 57% increase (p < 0.01) in microglia in 7 schizophrenics (139 +/- 6 cells/mm2) compared with 10 controls (88 +/- 5 cells/mm2). In area 24 the same trend was evident, but the results did not reach significance. Microglial number was further analyzed for each cortical layer, which confirmed the overall pattern. For all areas, numerical density of astroglia showed no significant differences between schizophrenics and controls. Cortical thickness was measured in all areas and total neuronal numerical density was estimated for area 22. Again, no significant differences were found between schizophrenics and controls. This study demonstrates a specific increase in the numerical density of HLA-DR+ microglia in temporal and frontal cortex of chronic schizophrenics, not related to aging, which might be implicated in possible changes in cortical neuropil architecture in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Brain Res. Bull. 2001 Jul 55: 611-8 |
| PMID | 11576757 |
| Title | A quantitative immunohistochemical study of astrocytes in the entorhinal cortex in schizophrenia, bipolar disorder and major depression: absence of significant astrocytosis. |
| Abstract | A number of macroscopic changes have been reported in the temporal lobe in schizophrenia. We have evaluated the density of glial fibrillary acidic protein (GFAP)-positive astrocytes in cortical layers 2 through 6 in the intermediate subarea of entorhinal cortex in two cohorts: the first, 15 cases, made up of schizophrenic (n = 7) and normal nonpsychiatric control subjects (n = 8), and the second, 56 cases, composed of schizophrenic (n = 14), bipolar disorder (n = 13), major depressive (n = 14) and normal control subjects (n = 15). No significant difference in density of GFAP-positive astrocytes was detected between the psychiatric diagnostic groups and the normal controls in either of the two cohorts. In both cohorts there was a positive correlation between increasing age and astrocytic density which reached statistical significance in only the larger cohort (r = 0.38, p = 0.004). Our results find no evidence for astrocytosis in the entorhinal cortex in several mental illnesses. Although other studies have reported macroscopic and other structural abnormalities in this region, we have not detected astrocytic proliferation, which is a typical hallmark of atrophy and/or progressive neuronal loss. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Brain Res. Bull. 2001 Jul 55: 611-8 |
| PMID | 11576757 |
| Title | A quantitative immunohistochemical study of astrocytes in the entorhinal cortex in schizophrenia, bipolar disorder and major depression: absence of significant astrocytosis. |
| Abstract | A number of macroscopic changes have been reported in the temporal lobe in schizophrenia. We have evaluated the density of glial fibrillary acidic protein (GFAP)-positive astrocytes in cortical layers 2 through 6 in the intermediate subarea of entorhinal cortex in two cohorts: the first, 15 cases, made up of schizophrenic (n = 7) and normal nonpsychiatric control subjects (n = 8), and the second, 56 cases, composed of schizophrenic (n = 14), bipolar disorder (n = 13), major depressive (n = 14) and normal control subjects (n = 15). No significant difference in density of GFAP-positive astrocytes was detected between the psychiatric diagnostic groups and the normal controls in either of the two cohorts. In both cohorts there was a positive correlation between increasing age and astrocytic density which reached statistical significance in only the larger cohort (r = 0.38, p = 0.004). Our results find no evidence for astrocytosis in the entorhinal cortex in several mental illnesses. Although other studies have reported macroscopic and other structural abnormalities in this region, we have not detected astrocytic proliferation, which is a typical hallmark of atrophy and/or progressive neuronal loss. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Brain Behav. Immun. 2001 Dec 15: 388-400 |
| PMID | 11782105 |
| Title | Immunohistochemical localization of phosphorylated glial fibrillary acidic protein in the prefrontal cortex and hippocampus from patients with schizophrenia, bipolar disorder, and depression. |
| Abstract | Increasingly, abnormalities of glial cell function have been implicated in pathological studies of the major mental illnesses (schizophrenia, bipolar disorder, and major depression). In a recent proteomic study, four isoforms of astrocytic glial fibrillary acidic protein (GFAP) were decreased in one or more of these diseases. In the current study, we sought to determine the immunohistochemical localization of phosphorylated GFAP (pGFAP) in the prefrontal cortex and hippocampus and to describe possible disease-related changes in the distribution of pGFAP containing astrocytes. In the prefrontal cortex, interlaminar astrocytes in layer I and stellate astrocytes in layers II and VI were labeled. Labeled cells were also present adjacent to blood vessels in the gyral white matter and in underlying white matter generally. In the hippocampus, labeled cells were present in the polymorphic layer of the dentate gyrus. In the prefrontal cortex, schizophrenia and major depression were characterized by decreased labeling of astrocytes adjacent to blood vessels. There were no significant differences between the diagnostic groups in the other prefrontal layers or in the hippocampus. These results suggest that reduced numbers or functional regulation of pGFAP containing astrocytes occurs in schizophrenia and major depression. The mechanism by which this deficit occurs is not known, but it may adversely effect the regulation of neuronal metabolism, communication, and response to injury. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Schizophr. Res. 2002 Oct 57: 127-38 |
| PMID | 12223243 |
| Title | Layer-specific reductions in GFAP-reactive astroglia in the dorsolateral prefrontal cortex in schizophrenia. |
| Abstract | Neuroimaging studies have implicated the prefronto-striatal loop as a substrate for the cognitive deficits in schizophrenia (SCHZ). Postmortem morphometric studies reveal that layers III and V of the dorsolateral prefrontal cortex (dlPFC), which gave rise to glutamatergic projections to neostriatum, demonstrate the most structural pathology in this region of the SCHZ. These neuronal alterations in SCHZ are not accompanied by marked glial changes as revealed by Nissl staining. We examined the glial-type specific pathology in SCHZ by analyzing the glial fibrillary acidic protein- (GFAP) immunoreactive astroglia in contrast to the Nissl-stained general pool of glial cells in dlPFC (area 9) from 9 subjects with SCHZ and 15 psychiatrically normal control subjects. In layer V of the dlPFC in SCHZ, there was a significant 32% reduction in the GFAP-area fraction, 81% increase in the density of the GFAP-positive cell bodies and a 14% decrease in the width of the cortical layer V, as compared to the control subjects. None of these parameters were affected in layers III and IV in the SCHZ. Therefore, only subtle, type- and layer-specific glial pathology is present in the dlPFC in SCHZ. Astroglial pathology in dlPFC may reflect disturbances of the neuron-glia interactions in layer V and may be related to the dysfunctional prefronto-striatal circuits, dopaminergic alterations and cognitive pathology in SCHZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | Mol. Psychiatry 2002 -1 7: 633-40 |
| PMID | 12140787 |
| Title | Human influenza viral infection in utero alters glial fibrillary acidic protein immunoreactivity in the developing brains of neonatal mice. |
| Abstract | Epidemiological reports describe a strong association between prenatal human influenza viral infection and later development of schizophrenia. Postmodern human brain studies, however, indicate a lack of gliosis in schizophrenic brains presumably secondary to absence of glial cells during the second trimester viral infection in utero. We hypothesized that human influenza infection in day 9 pregnant mice would alter the expression of glial fibrillary acidic protein (GFAP, an important marker of gliosis, neuron migration, and reactive injury) in developing brains of postnatal days 0, 14 and 35 mice. Determination of cellular GFAP immunoreactivity (IR) expressed as cell density in cortex and hippocampus of control and experimental brains showed increases in GFAP-positive density in exposed cortical (P = 0.03 day 14 vs control) and hippocampal cells (P = 0.035 day 14, P = 0.034 day 35). Similarly, ependymal cell layer GFAP-IR cell counts showed increases with increasing brain age from day 0, to days 14 and 35 in infected groups (P = 0.037, day 14) vs controls. The GFAP-positive cells in prenatally exposed brains showed 'hypertrophy' and more stellate morphology. These results implicate a significant role of prenatal human influenza viral infection on subsequent gliosis, which persists throughout brain development in mice from birth to adolescence. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Mol. Psychiatry 2002 -1 7: 633-40 |
| PMID | 12140787 |
| Title | Human influenza viral infection in utero alters glial fibrillary acidic protein immunoreactivity in the developing brains of neonatal mice. |
| Abstract | Epidemiological reports describe a strong association between prenatal human influenza viral infection and later development of schizophrenia. Postmodern human brain studies, however, indicate a lack of gliosis in schizophrenic brains presumably secondary to absence of glial cells during the second trimester viral infection in utero. We hypothesized that human influenza infection in day 9 pregnant mice would alter the expression of glial fibrillary acidic protein (GFAP, an important marker of gliosis, neuron migration, and reactive injury) in developing brains of postnatal days 0, 14 and 35 mice. Determination of cellular GFAP immunoreactivity (IR) expressed as cell density in cortex and hippocampus of control and experimental brains showed increases in GFAP-positive density in exposed cortical (P = 0.03 day 14 vs control) and hippocampal cells (P = 0.035 day 14, P = 0.034 day 35). Similarly, ependymal cell layer GFAP-IR cell counts showed increases with increasing brain age from day 0, to days 14 and 35 in infected groups (P = 0.037, day 14) vs controls. The GFAP-positive cells in prenatally exposed brains showed 'hypertrophy' and more stellate morphology. These results implicate a significant role of prenatal human influenza viral infection on subsequent gliosis, which persists throughout brain development in mice from birth to adolescence. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | Schizophr. Res. 2004 Apr 67: 293-5; author reply 297-9 |
| PMID | 14984890 |
| Title | GFAP-immunopositive astrocytes in schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Schizophr. Res. 2004 Aug 69: 317-23 |
| PMID | 15469203 |
| Title | Glial fibrillary acidic protein is reduced in cerebellum of subjects with major depression, but not schizophrenia. |
| Abstract | Glial fibrillary acidic protein (GFAP) is a major protein of astrocyte intermediate filaments and a specific marker for astrocytes. Alterations in levels of GFAP may reflect pathological regulation of neuronal function and survival as well as abnormal synaptogenesis and neurotransmission. We employed quantitative gel electrophoresis and Western blotting to measure levels of GFAP in cerebella of 60 subjects divided equally among schizophrenia, bipolar disorder, major depression, and normal controls. GFAP levels were reduced by 32%, 17% and 14.5% in depressed, bipolar, and schizophrenic cerebella, respectively, versus controls. Only the depressed value was significantly different (p=0.015 Post-hoc Bonferroni test). Measurement of beta-actin levels showed no differences between the various groups. No significant effects of confounding variables were found. This is the first demonstration of GFAP reductions in cerebellum of subjects with mood disorders and schizophrenia, thereby adding to the reports of reductions in GFAP/glial cell counts in other brain regions of subjects with major depression, thus suggesting a downregulation of glial function in this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | Schizophr. Res. 2004 Aug 69: 317-23 |
| PMID | 15469203 |
| Title | Glial fibrillary acidic protein is reduced in cerebellum of subjects with major depression, but not schizophrenia. |
| Abstract | Glial fibrillary acidic protein (GFAP) is a major protein of astrocyte intermediate filaments and a specific marker for astrocytes. Alterations in levels of GFAP may reflect pathological regulation of neuronal function and survival as well as abnormal synaptogenesis and neurotransmission. We employed quantitative gel electrophoresis and Western blotting to measure levels of GFAP in cerebella of 60 subjects divided equally among schizophrenia, bipolar disorder, major depression, and normal controls. GFAP levels were reduced by 32%, 17% and 14.5% in depressed, bipolar, and schizophrenic cerebella, respectively, versus controls. Only the depressed value was significantly different (p=0.015 Post-hoc Bonferroni test). Measurement of beta-actin levels showed no differences between the various groups. No significant effects of confounding variables were found. This is the first demonstration of GFAP reductions in cerebellum of subjects with mood disorders and schizophrenia, thereby adding to the reports of reductions in GFAP/glial cell counts in other brain regions of subjects with major depression, thus suggesting a downregulation of glial function in this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Neurosci. Res. 2004 Mar 48: 345-53 |
| PMID | 15154680 |
| Title | Neonatal impact of leukemia inhibitory factor on neurobehavioral development in rats. |
| Abstract | Cytokines have been implicated in the etiology or pathology of various psychiatric diseases of developmental origin such as autism and schizophrenia. Leukemia inhibitory factor (LIF) is induced by a variety of brain insults and known to have many influences on mature and immature nervous system. Here, we assessed the neurobehavioral and pathological consequences of peripheral administration of LIF in newborn rats. Subcutaneous LIF injection induced STAT3 phosphorylation in many brain regions and increased glial fibrillary acidic protein (GFAP) immunoreactivity in the neocortex, suggesting that LIF had direct effects in the central nervous system. The LIF-treated rats displayed decreased motor activity during juvenile stages, and developed abnormal prepulse inhibition in the acoustic startle test during and after adolescence. They displayed normal learning ability in active avoidance test, however. Brain neuronal structures and startle responses were grossly normal, except for the cortical astrogliosis during neonatal LIF administration. These results indicate that LIF induction in the periphery of the infant has a significant, but discrete impact on neurobehavioral development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | Neuroscience 2005 -1 133: 453-61 |
| PMID | 15885920 |
| Title | Glial fibrillary acidic protein mRNA levels in the cingulate cortex of individuals with depression, bipolar disorder and schizophrenia. |
| Abstract | Recent studies have shown a decrease in glial number and glial fibrillary acidic protein (GFAP) levels in the frontal and cingulate cortices of individuals with mood disorders and schizophrenia. In an attempt to verify and expand these findings we examined GFAP messenger ribonucleic acid (mRNA) levels in postmortem sections of the anterior cingulate cortex (ACC) from the Stanley Neuropathology Consortium (SNC). The consortium consists of 15 cases in each of four groups (schizophrenia, bipolar disorder, non-psychotic depression and unaffected controls). By in situ hybridization, we found higher levels of GFAP mRNA in white matter and at the pial surface as compared with gray matter levels in all cases. In the white matter of ACC we detected a significant effect of diagnosis (P<0.04) with GFAP mRNA levels decreased in individuals with schizophrenia and bipolar disorder as compared with normal controls. In the gray matter there was a significant effect of layer (P<0.01) with the highest levels of GFAP mRNA in layer VI in all groups. As in the white matter, the mean GFAP mRNA levels were decreased in individuals with schizophrenia and bipolar disorder as compared with the unaffected controls, however the difference failed to reach statistical significance. Thus, astrocytes positive for GFAP may contribute to the decrease in glial density previously described in subjects with major mental illness, however the relative contribution of astrocytes may vary with diagnosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | J. Neurol. Neurosurg. Psychiatr. 2006 Nov 77: 1284-7 |
| PMID | 17043297 |
| Title | Increased cerebrospinal fluid and serum levels of S100B in first-onset schizophrenia are not related to a degenerative release of glial fibrillar acidic protein, myelin basic protein and neurone-specific enolase from glia or neurones. |
| Abstract | To assess levels of glial fibrillar acidic protein (GFAP), myelin basic protein (MBP), neurone-specific enolase (NSE) and S100B in patients with first-onset schizophrenia. We investigated CSF and serum samples from 12 patients with first-onset schizophrenia and from 17 control subjects by ELISA (GFAP, MBP) or immunoluminometric sandwich assays (NSE, S100B). Patients with schizophrenia had significantly higher levels of S100B in CSF (p = 0.004; 2.73 (SD 0.80) v 1.92 (0.58) microg/l) and serum (p = 0.032; 0.09 (0.03) v 0.08 (0.02) microg/l) in comparison with those in the matched control group. No diagnosis-dependent differences of protein concentration were seen for GFAP, MBP and NSE. Our finding of increased levels of S100B in patients with schizophrenia without an indication for significant glial (GFAP, MBP) or neuronal (NSE) damage may be interpreted as indirect evidence for increased active secretion of S100B during acute psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | Neurosci. Lett. 2006 Sep 404: 276-81 |
| PMID | 16842914 |
| Title | Glial fibrillary acidic protein and glutamine synthetase in subregions of prefrontal cortex in schizophrenia and mood disorder. |
| Abstract | Several theories of schizophrenia suggest dysfunction in glutamate neurotransmission in higher brain regions such as the prefrontal cortex (PFC). Previous studies have investigated whether astroglial abnormalities could give rise to glutamate dysfunction using glial fibrillary acidic protein (GFAP) immunocytochemistry. We have used quantitative immunoautoradiography to measure glutamine synthetase (GS), the glial enzyme which recycles synaptic glutamate, as a more direct test of glial mechanisms of abnormal glutamate function in schizophrenia. We compared GS with GFAP immunoautoradiography in dorsolateral (area 9) and orbitofrontal (area 11/47) cortex. Optical density measures from film autoradiographs revealed an increase in GFAP immunoreactivity in area 9 in schizophrenia and a decrease in area 11/47 in both schizophrenia and bipolar disorder. The increase in GFAP in area 9 significantly correlated with lifetime antipsychotic drug treatment, whereas the reduction in area 11/47 occurred despite this effect. There were no changes in GS immunoreactivity in any psychiatric disorder. Regional and antigen-specific down-regulation of GFAP protein in OFC in schizophrenia and bipolar disorder may relate to disease mechanisms of psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | Aust N Z J Psychiatry 2006 Mar 40: 217-24 |
| PMID | 16476148 |
| Title | Regionally specific changes in levels of cortical S100beta in bipolar 1 disorder but not schizophrenia. |
| Abstract | To determine if levels of the glial-derived proteins S100beta and glial acidic fibrillary protein (GFAP) and the pro- and antiapoptotic proteins p53 and Bcl-2 were altered in the cortex of subjects with schizophrenia or bipolar 1 disorder. Levels of S100beta, GFAP, p53 and Bcl-2 were measured in cortex (Brodmann's Areas (BAs) 9, 10, 46 and 40) of control subjects and subjects with schizophrenia, bipolar 1 disorder and in the cortex of rats treated with haloperidol or lithium using protein-specific antibodies and western blot analysis. Levels of S100beta were decreased in BA 9 and increased in BA 40 from subjects with bipolar 1 disorder. Levels of this protein were not altered in other CNS regions, in schizophrenia or in the cortex of rats treated with haloperidol or lithium. No changes in levels of the other three proteins were detected across diagnoses. Regionally selective changes in cortical S100beta may be associated with the pathology of bipolar 1 disorder and may reflect derangements in neuronal death or survival. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Mar 144B: 129-58 |
| PMID | 17266109 |
| Title | Towards understanding the schizophrenia code: an expanded convergent functional genomics approach. |
| Abstract | Identifying genes for schizophrenia through classical genetic approaches has proven arduous. Here, we present a comprehensive convergent analysis that translationally integrates brain gene expression data from a relevant pharmacogenomic mouse model (involving treatments with a psychomimetic agent - phencyclidine (PCP), and an anti-psychotic - clozapine), with human genetic linkage data and human postmortem brain data, as a Bayesian strategy of cross validating findings. Topping the list of candidate genes, we have three genes involved in GABA neurotransmission (GABRA1, GABBR1, and GAD2), one gene involved in glutamate neurotransmission (GRIA2), one gene involved in neuropeptide signaling (TAC1), two genes involved in synaptic function (SYN2 and KCNJ4), six genes involved in myelin/glial function (CNP, MAL, MBP, PLP1, MOBP and GFAP), and one gene involved in lipid metabolism (LPL). These data suggest that schizophrenia is primarily a disorder of brain functional and structural connectivity, with GABA neurotransmission playing a prominent role. These findings may explain the EEG gamma band abnormalities detected in schizophrenia. The analysis also revealed other high probability candidates genes (neurotransmitter signaling, other structural proteins, ion channels, signal transduction, regulatory enzymes, neuronal migration/neurite outgrowth, clock genes, transcription factors, RNA regulatory genes), pathways and mechanisms of likely importance in pathophysiology. Some of the pathways identified suggest possible avenues for augmentation pharmacotherapy of schizophrenia with other existing agents, such as benzodiazepines, anticonvulsants and lipid modulating agents. Other pathways are new potential targets for drug development. Lastly, a comparison with our earlier work on bipolar disorder illuminates the significant molecular overlap between schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | Neurosci. Res. 2007 Feb 57: 248-58 |
| PMID | 17141345 |
| Title | Suppressive effect of clozapine but not haloperidol on the increases of neuropeptide-degrading enzymes and glial cells in MK-801-treated rat brain regions. |
| Abstract | MK-801, a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, produces neurotoxicity in adult rodent brain, and causes schizophrenia-like psychosis and cognitive dysfunction. Since neuropeptides and neuropeptide-degrading enzymes play important roles in cognitive function, we examined whether or not MK-801-induced schizophrenia-like psychosis is co-related with the changes of these enzymes in rat brain regions. In the present study, we investigated the effect of systemic treatment with MK-801 (0.5mg/kg) on neuropeptide-degrading enzymes, prolyl oligopeptidase (POP) and thimet oligopeptidase (EP 24.15), and glial marker proteins GFAP and CD11b in rat brain regions. The levels of POP and EP 24.15 activities increased significantly three days after treatment with MK-801 in the posterior cingulate/retrosplenial cortices (PC/RSC). Since atypical neuroleptic clozapine but not typical neuroleptic haloperidol prevents the MK-801-induced schizophrenia-like symptoms, we further examined the pretreated effects of the neuroleptics. Clozapine, but not haloperidol, significantly attenuated MK-801-induced changes in the levels of the neuropeptide-degrading enzymes. Immunohistochemical studies on GFAP and CD11b showed the increase in the PC/RSC of MK-801-treated rat brain and the pretreatment with clozapine suppressed these changes. Double immunostain experiments of EP 24.15 and GFAP antibodies demonstrated some co-localization of the neuropeptidase with astrocytes. The present findings suggest that change of neuropeptidases in the brain is in part correlated with changes of glial cells, and may play an important role in the control of schizophrenia-like psychotic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 23 | Schizophr. Res. 2008 Aug 103: 71-82 |
| PMID | 18562176 |
| Title | Cortical expression of glial fibrillary acidic protein and glutamine synthetase is decreased in schizophrenia. |
| Abstract | Altered expression of structural and functional molecules expressed by astrocytes may play a role in the pathophysiology of schizophrenia. We investigated the hypothesis that the astrocytic enzyme glutamine synthetase, involved in maintaining the glutamate-glutamine cycle, and the cytoskeletal molecule glial fibrillary acidic protein (GFAP) are abnormally expressed in schizophrenia. We used Western blot analysis to measure levels of glutamine synthetase and GFAP in several brain regions of subjects with schizophrenia and a comparison group. We found that glutamine synthetase protein expression was significantly decreased in the superior temporal gyrus, and both glutamine synthetase and GFAP were significantly reduced in the anterior cingulate cortex in schizophrenia. Neither molecule demonstrated altered expression in the dorsolateral prefrontal cortex, primary visual cortex, or hippocampus. Chronic treatment with haloperidol did not alter the expression of these molecules in the rat brain, suggesting that our findings are not due to a medication effect. These data support an astrocytic component to the pathophysiology of schizophrenia and suggest that astrocytic molecules involved in enzymatic activity and cytoskeletal integrity may have a role in disease-related abnormalities in this illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 24 | Behav. Brain Res. 2008 Aug 191: 190-201 |
| PMID | 18486243 |
| Title | Amphetamine sensitization in rats as an animal model of schizophrenia. |
| Abstract | Based on the 'endogenous dopamine sensitization' hypothesis of schizophrenia the present study employed a repeated amphetamine administration regime in order to investigate the behavioral, neurochemical and neuroanatomical consequences following short- and long-term withdrawal periods. The escalating amphetamine administration schedule consisted of three injections per day over a 6-day period with the dosage ranging from 1 to 8 mg/kg. It was demonstrated that following both short- (4 days) and long-term (66 days) withdrawal periods latent inhibition (LI) and prepulse inhibition (PPI), two translational paradigms highly relevant to schizophrenia, were disrupted. A challenge injection verified sensitization in two different cohorts of animals at 40 and 70 days following cessation of treatment. Neurochemical evaluation demonstrated a reduction in dopamine levels in the caudate-putamen and nucleus accumbens core and shell as well as an enhanced utilization ratio in the caudate-putamen after both withdrawal periods. Similar to the findings from post-mortem studies of brains of schizophrenic patients, a downregulation of glutamic acid decarboxylase 67 (GAD67) immunoreactivity was found in the hippocampus, prefrontal cortex, thalamus, and amygdala in amphetamine pretreated animals following longer withdrawal periods. This was not accompanied by enhanced neurotoxicity or reactive gliosis as demonstrated by the immunohistological analysis using the apoptotic marker activated Caspase-3 and GFAP (glial fibrillary acidic protein; a marker for astrocytes) following both short- and long-term withdrawal periods. In conclusion, it is suggested that these findings constitute a highly reliable and valid animal model of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 25 | Behav. Brain Res. 2008 Aug 191: 190-201 |
| PMID | 18486243 |
| Title | Amphetamine sensitization in rats as an animal model of schizophrenia. |
| Abstract | Based on the 'endogenous dopamine sensitization' hypothesis of schizophrenia the present study employed a repeated amphetamine administration regime in order to investigate the behavioral, neurochemical and neuroanatomical consequences following short- and long-term withdrawal periods. The escalating amphetamine administration schedule consisted of three injections per day over a 6-day period with the dosage ranging from 1 to 8 mg/kg. It was demonstrated that following both short- (4 days) and long-term (66 days) withdrawal periods latent inhibition (LI) and prepulse inhibition (PPI), two translational paradigms highly relevant to schizophrenia, were disrupted. A challenge injection verified sensitization in two different cohorts of animals at 40 and 70 days following cessation of treatment. Neurochemical evaluation demonstrated a reduction in dopamine levels in the caudate-putamen and nucleus accumbens core and shell as well as an enhanced utilization ratio in the caudate-putamen after both withdrawal periods. Similar to the findings from post-mortem studies of brains of schizophrenic patients, a downregulation of glutamic acid decarboxylase 67 (GAD67) immunoreactivity was found in the hippocampus, prefrontal cortex, thalamus, and amygdala in amphetamine pretreated animals following longer withdrawal periods. This was not accompanied by enhanced neurotoxicity or reactive gliosis as demonstrated by the immunohistological analysis using the apoptotic marker activated Caspase-3 and GFAP (glial fibrillary acidic protein; a marker for astrocytes) following both short- and long-term withdrawal periods. In conclusion, it is suggested that these findings constitute a highly reliable and valid animal model of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 26 | J. Mol. Neurosci. 2009 May 38: 2-11 |
| PMID | 18836851 |
| Title | Discoidin domain receptor 1, a tyrosine kinase receptor, is upregulated in an experimental model of remyelination and during oligodendrocyte differentiation in vitro. |
| Abstract | The discoidin domain receptor (DDR1) is highly expressed in oligodendrocytes during the neurodevelopmental myelination process and is genetically associated to schizophrenia. In this study, we aimed to further assess the involvement of DDR1 in both remyelination and oligodendrocyte differentiation. In the mouse model of demyelination-remyelination induced by oral administration of cuprizone, in situ hybridization showed an upregulation of the DDR1 gene in three different white matter areas (corpus callosum, dorsal fornix, and external capsule) during the remyelination period. Moreover, real time reverse transcriptase polymerase chain reaction showed that the increase in DDR1 messenger RNA (mRNA) was strongly correlated with the number of DDR1-positive cells in the corpus callosum (Spearman coefficient = 0.987, P = 0.013). Cells positive for DDR1 mRNA were also positive for oligodendrocyte markers (OLIG2, carnosine, and APC) but not for markers of oligodendrocyte precursors (NG2), myelin markers (CNPase), microglia (CD11b), or reactive glia (GFAP). Differentiation of a human oligodendroglial cell line, HOG16, was associated with an increase in mRNA expression of DDR1 and several myelin proteins (MBP and MOBP) but not other proteins (APC and CNPase). Here, we demonstrate that DDR1 is upregulated in vitro and in vivo when oligodendrocyte myelinating machinery is activated. Further studies are needed to identify the specific molecular pathway. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 27 | BMC Psychiatry 2009 -1 9: 17 |
| PMID | 19405953 |
| Title | Proteome analysis of schizophrenia patients Wernicke's area reveals an energy metabolism dysregulation. |
| Abstract | schizophrenia is likely to be a consequence of DNA alterations that, together with environmental factors, will lead to protein expression differences and the ultimate establishment of the illness. The superior temporal gyrus is implicated in schizophrenia and executes functions such as the processing of speech, language skills and sound processing. We performed an individual comparative proteome analysis using two-dimensional gel electrophoresis of 9 schizophrenia and 6 healthy control patients' left posterior superior temporal gyrus (Wernicke's area - BA22p) identifying by mass spectrometry several protein expression alterations that could be related to the disease. Our analysis revealed 11 downregulated and 14 upregulated proteins, most of them related to energy metabolism. Whereas many of the identified proteins have been previously implicated in schizophrenia, such as fructose-bisphosphate aldolase C, creatine kinase and neuron-specific enolase, new putative disease markers were also identified such as dihydrolipoyl dehydrogenase, tropomyosin 3, breast cancer metastasis-suppressor 1, heterogeneous nuclear ribonucleoproteins C1/C2 and phosphate carrier protein, mitochondrial precursor. Besides, the differential expression of peroxiredoxin 6 (PRDX6) and glial fibrillary acidic protein (GFAP) were confirmed by western blot in schizophrenia prefrontal cortex. Our data supports a dysregulation of energy metabolism in schizophrenia as well as suggests new markers that may contribute to a better understanding of this complex disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 28 | Schizophr. Res. 2009 Jul 112: 54-64 |
| PMID | 19447584 |
| Title | Subcortical oligodendrocyte- and astrocyte-associated gene expression in subjects with schizophrenia, major depression and bipolar disorder. |
| Abstract | Deficits in the expression of oligodendrocyte and myelin genes have been described in numerous cortical regions in schizophrenia and affective disorders; however, relatively little attention has been paid to subcortical structures. Here we employed quantitative real time PCR to examine the mRNA expression of 17 genes that are expressed by oligodendrocyte precursors (OLPs) and their derivatives, including astrocytes. Four subcortical regions were examined (the anteroventral (AV) and mediodorsal thalamic nuclei (MDN), internal capsule (IC) and putamen (Put)) in postmortem material from subjects (age 25-68 at time of death) with no known psychiatric history (NCs) as well as in subjects with schizophrenia (SZ), major depressive disorder (MDD), and bipolar disorder (BPD). In all regions examined, genes expressed after the terminal differentiation of oligodendrocytes tended to have lower levels of mRNA expression in subjects with SZ compared to NCs. These differences were statistically significant across regions for four genes (CNP, GALC, MAG and MOG) and approached significance for TF. No genes were under expressed in MDD. Only TF was under expressed in BPD and only in the IC. In contrast, two astrocyte-associated genes (GFAP and ALDH1L1) had higher mean expression levels across regions in all psychiatric groups relative to NCs. These differences reached statistical significance for SZ and MDD relative to NCs. There were no age by diagnosis interactions. The majority of age regressions had negative slopes for the expression of oligodendrocyte-associated genes. GFAP but not ALDH1L1 expression was significantly and positively correlated with age in the MDN, AV and Put. Across subject groups the expression of both astrocyte genes was highly correlated with cumulative neuroleptic exposure in all regions except the Put. Significant positive correlations were also observed in some regions between cumulative neuroleptic exposure and the expression of genes associated with mature oligodendrocytes as well as with bipotential OLPs. Multiple negative correlations were observed between the mRNA expression of astrocyte genes and genes expressed by terminally differentiated oligodendrocytes. These data are discussed in the context of myelin turnover and potential effects of psychiatric illness as well as medications on the developmental fate of OLPs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 29 | Neuropathology 2009 Dec 29: 684-8 |
| PMID | 19170897 |
| Title | Clinicopathological study of early progressive multifocal leukoencephalopathy incidentally found in a schizophrenia patient. |
| Abstract | A 58-year-old Japanese man developed psychomotor excitement and hallucinatory paranoia at age 53, which gradually developed to residual schizophrenia. He was administered various common tranquilizers until death. Myelodysplastic syndrome was noted 10 months before death. A routine autopsy was performed. The brain weighed 1365 g, and macroscopic observation revealed no remarkable findings. However, microscopic examination disclosed cells with enlarged and basophilic nuclei, and unusual astrocytes in the demyelinated foci, especially at the corticomedullary junctions in the temporal and occipital lobes. On the other hand, the white matter was relatively intact. Immunohistochemical analysis using anti-JC virus protein, VP-1 antibody, demonstrated JC virus-infected cells in not only abnormal glial cells and neurons but also normal-looking cells, which are suggestive of progressive multifocal leukoencephalopathy (PML). Immunostaining for GFAP revealed severe gliosis and some scattered abnormal enlarged nuclear cells in the lesions. Some clusters of CD8-positive lymphocytes were seen, which kill infected cells. PML could be considered a short-term disease preceding death, as "incidental PML" in this case. This is a rare autopsy case of early PML occurring in a schizophrenia patient with PML. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 30 | Int. J. Dev. Neurosci. 2009 May 27: 233-41 |
| PMID | 19429388 |
| Title | Early maternal deprivation in rats induces gender-dependent effects on developing hippocampal and cerebellar cells. |
| Abstract | Adult animals submitted to a single prolonged episode of maternal deprivation [24h, postnatal day 9-10] show behavioral alterations that resemble specific symptoms of schizophrenia. According to the neurodevelopmental theory, these behavioral deficits might be mediated by detrimental neurodevelopmental processes that might be associated, at least partially, with stress-induced corticosterone responses. In order to address this hypothesis, we have focused on the hippocampus and cerebellar cortex, two brain regions that show high density of glucocorticoid receptors, and analyzed possible neuronal and glial alterations by immunohistochemical techniques. To evaluate the presence of degenerated neurons we used Fluoro-Jade-C (FJ-C) staining and for the study of astrocytes we employed glial fibrillary acidic protein (GFAP). Within control animals, females showed significantly more GFAP positive cells than males and a trend towards more FJ-C positive cells. Maternal deprivation induced neuronal degeneration and astroglial changes in the hippocampus and cerebellar cortex of neonatal rats that, in general, were more marked in males. This differential effect may be attributable to a greater vulnerability of males to this kind of early environmental insult and/or to sex-dependent differences in the onset and/or progression of the effects. The present experimental procedure may be instrumental in elucidating sex-dependent mechanisms of neurodevelopmental psychiatric disorders with a basis in early environmental insults. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 31 | Schizophr. Res. 2010 Jun 119: 164-74 |
| PMID | 20346631 |
| Title | Haloperidol activates quiescent oligodendroglia precursor cells in the adult mouse brain. |
| Abstract | Recent human studies suggest that abnormal development of oligodendrocytes (OLs) is an important component in the pathophysiology of schizophrenia. However, less information is available regarding effects of antipsychotics on OLs' development. In the present study, young adult C57BL/6 mice were given haloperidol (HAL; 2mg/kg/day) in their drinking water for three or six weeks. At the conclusion of the drug treatment, mice were sacrificed and the numbers of NG2- and Olig2-expressing cells in the brain regions of the corpus callosum, hippocampus and cerebral cortex were quantified. NG2 is a specific marker for oligodendroglia precursor cells (OPCs); Olig2 marks glial progenitors. HAL treatment for three weeks increased the number of NG2-expressing cells in the corpus callosum; HAL treatment for three and six weeks increased the numbers of Olig2-expressing cells in all three brain regions and increased the levels of Olig2 expression in the same brain regions. These results suggest that HAL treatment activates adult OPCs, which divide infrequently under normal conditions but respond to a variety of insulting factors by proliferation and differentiation. However, our further observations showed no changes in the number of mature OLs and the amount of myelin basic protein in HAL-treated mice, suggesting the drug treatment has no effect on the maturation of OLs. In addition, HAL treatment did not increase the numbers of GFAP- and CD68-expressing cells, suggesting that no gliosis and inflammatory responses occurred while the drug activated the quiescent OPCs in adult brain. These results suggest that HAL treatment may target the development of OLs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 32 | Bipolar Disord 2010 Aug 12: 541-9 |
| PMID | 20712756 |
| Title | Amygdala astrocyte reduction in subjects with major depressive disorder but not bipolar disorder. |
| Abstract | Several magnetic resonance imaging studies have found changes in amygdala volumes in adults with mood disorders. The cellular basis for these changes has not been explored in detail. Specifically, it is not known whether differences in the density and/or volume of neurons or glial cells contribute to tissue volume changes seen on magnetic resonance images. Postmortem amygdala samples were obtained from the Stanley Foundation Neuropathology Consortium from subjects diagnosed with bipolar disorder (n = 10), major depressive disorder (n = 11), and schizophrenia (n = 9), and from normal controls (n = 14). Samples were first stained with glial fibrillary acidic protein (GFAP) and counter-stained with hematoxylin to ascertain neuron and glia (astrocyte) densities. No significant differences in neuronal densities were found between groups. However, a reduction in the density of GFAP immunoreactive astrocytes was observed in the amygdala of subjects with major depressive disorder compared to the bipolar disorder, schizophrenia, and normal control postmortem samples. A decrease in density of GFAP immunoreactive astrocytes in the amygdala of depressed subjects is consistent with prior histologic reports and might contribute to amygdala volume reductions reported in several in vivo neuroimaging studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 33 | J. Anat. 2010 Oct 217: 324-33 |
| PMID | 20408906 |
| Title | When cortical development goes wrong: schizophrenia as a neurodevelopmental disease of microcircuits. |
| Abstract | schizophrenia probably has a developmental origin. This review refers to three of our published series of studies related to this hypothesis: loss of dendritic spines on cerebral neocortical pyramidal neurons, decreased numerical density of glutamatergic neurons, and microgliosis. First, brains of schizophrenic patients and non-schizophrenic controls were obtained post mortem and blocks of multiple cortical areas impregnated with a Rapid Golgi method. Spines were counted on the dendrites of pyramidal neurons of which the soma was in layer III (which takes part in corticocortical connectivity) and which met strict criteria for impregnation quality. Data were obtained blind: diagnoses were only revealed by a third party after measurements were completed. The mean spine count in all cortical areas studied in the control series was 243 mm(-1) of dendrite and in the schizophrenics 108. Measurements in frontal and temporal association cortex showed the greatest reduction in spine number in schizophrenia (299 in control frontal cortex and 101 in schizophrenics, and 276 mm(-1) in control temporal cortex and 125 in schizophrenics). There was no correlation of spine loss with age at death. Our results support the concept of a neurodevelopmental defect in the neuropil affecting glutamatergic neurons in schizophrenia and may help to explain loss of cortical volume without loss of neurons. In a second part of our study we used an antibody to the kainate receptor subunit GluR 5/6/7 and showed a decrease in numerical density of presumed glutamatergic neurons in schizophrenic orbitofrontal cortex. Finally, as glia play a major role in the developing nervous system, we investigated whether schizophrenia was associated with glial changes in frontal and temporal cortex. Astroglia and microglia were identified in schizophrenic and control brains, using antibodies to glial fibrillary acidic protein (GFAP) and class II human leucocyte antigen (HLA-DR), respectively. Significant increases were found in microglial numerical density in schizophrenics compared with controls: 28% in frontal area 9 (115 cells mm(-2) compared with 89), and a 57% increase in temporal area 22 (139 cells mm(-2) compared with 88). For both areas, astroglia showed no significant differences between schizophrenics and controls. No significant differences were found in cortical thickness or total neuronal numerical density between the two groups. This specific increase in numerical density of microglia in temporal and frontal cortex of chronic schizophrenics, not related to aging, could be related to possible changes in cortical neuropil architecture as revealed by loss of dendritic spines. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 34 | J. Anat. 2010 Oct 217: 324-33 |
| PMID | 20408906 |
| Title | When cortical development goes wrong: schizophrenia as a neurodevelopmental disease of microcircuits. |
| Abstract | schizophrenia probably has a developmental origin. This review refers to three of our published series of studies related to this hypothesis: loss of dendritic spines on cerebral neocortical pyramidal neurons, decreased numerical density of glutamatergic neurons, and microgliosis. First, brains of schizophrenic patients and non-schizophrenic controls were obtained post mortem and blocks of multiple cortical areas impregnated with a Rapid Golgi method. Spines were counted on the dendrites of pyramidal neurons of which the soma was in layer III (which takes part in corticocortical connectivity) and which met strict criteria for impregnation quality. Data were obtained blind: diagnoses were only revealed by a third party after measurements were completed. The mean spine count in all cortical areas studied in the control series was 243 mm(-1) of dendrite and in the schizophrenics 108. Measurements in frontal and temporal association cortex showed the greatest reduction in spine number in schizophrenia (299 in control frontal cortex and 101 in schizophrenics, and 276 mm(-1) in control temporal cortex and 125 in schizophrenics). There was no correlation of spine loss with age at death. Our results support the concept of a neurodevelopmental defect in the neuropil affecting glutamatergic neurons in schizophrenia and may help to explain loss of cortical volume without loss of neurons. In a second part of our study we used an antibody to the kainate receptor subunit GluR 5/6/7 and showed a decrease in numerical density of presumed glutamatergic neurons in schizophrenic orbitofrontal cortex. Finally, as glia play a major role in the developing nervous system, we investigated whether schizophrenia was associated with glial changes in frontal and temporal cortex. Astroglia and microglia were identified in schizophrenic and control brains, using antibodies to glial fibrillary acidic protein (GFAP) and class II human leucocyte antigen (HLA-DR), respectively. Significant increases were found in microglial numerical density in schizophrenics compared with controls: 28% in frontal area 9 (115 cells mm(-2) compared with 89), and a 57% increase in temporal area 22 (139 cells mm(-2) compared with 88). For both areas, astroglia showed no significant differences between schizophrenics and controls. No significant differences were found in cortical thickness or total neuronal numerical density between the two groups. This specific increase in numerical density of microglia in temporal and frontal cortex of chronic schizophrenics, not related to aging, could be related to possible changes in cortical neuropil architecture as revealed by loss of dendritic spines. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 35 | J. Anat. 2010 Oct 217: 324-33 |
| PMID | 20408906 |
| Title | When cortical development goes wrong: schizophrenia as a neurodevelopmental disease of microcircuits. |
| Abstract | schizophrenia probably has a developmental origin. This review refers to three of our published series of studies related to this hypothesis: loss of dendritic spines on cerebral neocortical pyramidal neurons, decreased numerical density of glutamatergic neurons, and microgliosis. First, brains of schizophrenic patients and non-schizophrenic controls were obtained post mortem and blocks of multiple cortical areas impregnated with a Rapid Golgi method. Spines were counted on the dendrites of pyramidal neurons of which the soma was in layer III (which takes part in corticocortical connectivity) and which met strict criteria for impregnation quality. Data were obtained blind: diagnoses were only revealed by a third party after measurements were completed. The mean spine count in all cortical areas studied in the control series was 243 mm(-1) of dendrite and in the schizophrenics 108. Measurements in frontal and temporal association cortex showed the greatest reduction in spine number in schizophrenia (299 in control frontal cortex and 101 in schizophrenics, and 276 mm(-1) in control temporal cortex and 125 in schizophrenics). There was no correlation of spine loss with age at death. Our results support the concept of a neurodevelopmental defect in the neuropil affecting glutamatergic neurons in schizophrenia and may help to explain loss of cortical volume without loss of neurons. In a second part of our study we used an antibody to the kainate receptor subunit GluR 5/6/7 and showed a decrease in numerical density of presumed glutamatergic neurons in schizophrenic orbitofrontal cortex. Finally, as glia play a major role in the developing nervous system, we investigated whether schizophrenia was associated with glial changes in frontal and temporal cortex. Astroglia and microglia were identified in schizophrenic and control brains, using antibodies to glial fibrillary acidic protein (GFAP) and class II human leucocyte antigen (HLA-DR), respectively. Significant increases were found in microglial numerical density in schizophrenics compared with controls: 28% in frontal area 9 (115 cells mm(-2) compared with 89), and a 57% increase in temporal area 22 (139 cells mm(-2) compared with 88). For both areas, astroglia showed no significant differences between schizophrenics and controls. No significant differences were found in cortical thickness or total neuronal numerical density between the two groups. This specific increase in numerical density of microglia in temporal and frontal cortex of chronic schizophrenics, not related to aging, could be related to possible changes in cortical neuropil architecture as revealed by loss of dendritic spines. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 36 | Zh Nevrol Psikhiatr Im S S Korsakova 2011 -1 111: 54-7 |
| PMID | 21423116 |
| Title | [Effect of haloperidol and risperidone on neuromarkers and indices of endothelial dysfunction in patients with acute schizophrenia]. |
| Abstract | Effect of haloperidol and risperidone on positive, negative, neurocognitive disorders, biological parameters and neurodestruction-neuroreparation processes have been studied in 23 patients with the first episode of paranoid schizophrenia. Risperidone, along with high therapeutic effect towards positive, negative, neurocognitive disorders, is able to reduce brain neurodestruction markers as well as to improve protective-compensatory processes directed to the neuroplasticity restoration. There were correlations between biological parameters studied: the higher were levels of GFAP and antibodies to NR2 subunit of NMDA receptors, the higher were BDNF and NO values. The association between parameters studied and psychopathological disorders measured with the PANSS has been found in patients treated with risperidone. The mentioned correlations were not observed in patients treated with haloperidol. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 37 | Brain Behav. Immun. 2012 Nov 26: 1288-99 |
| PMID | 22960545 |
| Title | Behaviour and hippocampus-specific changes in spiny mouse neonates after treatment of the mother with the viral-mimetic Poly I:C at mid-pregnancy. |
| Abstract | Epidemiological studies have suggested a link between prenatal exposure to bacterial or viral infections and subsequent development of mental disorders such as schizophrenia and autism. Animal models to study the prenatal origin of such outcomes of pregnancy have largely used conventional rodents which are immature at birth compared to the human neonate, and doses of the infective agent (i.e., lipopolysaccharide, Poly I:C) have been large enough to cause sickness behaviour in the mother. In this study we have used the spiny mouse (Acomys cahirinus) whose offspring have completed organogenesis at birth, and a single subcutaneous injection of a low (0.5mg/kg) dose of polyriboinosinic-polyribocytidilic acid (Poly I:C) at mid gestation (20 days, term is 39 days). The treatment had no effect on maternal, fetal or neonatal survival, or postnatal growth of the offspring. However, offspring showed significant impairments in non-spatial memory and learning tasks, and motor activity. Brain histology examined at 1 and 100 days of age revealed significant decreases in reelin, increased GFAP expression, and increased numbers of activated microglia, specifically in the hippocampus. This study provides evidence that a prenatal subclinical infection can have profound effects on brain development that are long-lasting. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 38 | Front Biosci (Elite Ed) 2012 -1 4: 2845-53 |
| PMID | 22652683 |
| Title | Effects of in utero endotoxemia on the ovine fetal brain: a model for schizophrenia? |
| Abstract | Infections during pregnancy can adversely affect the development of the fetal brain. This may contribute to disease processes such as schizophrenia in later life. Changes in the (cyto-) architecture of the anterior cingulate cortex (ACC), particularly in GABA-ergic interneurons, play a role in the pathogenesis of schizophrenia. We hypothesized that exposure to infection during pregnancy could result in cyto-architectural changes in the fetal ACC, similar to the pathogenesis seen in schizophrenia. Fetal sheep of 110 days GA (term=150 days GA) received an intravenous injection of 100 ng or 500 ng lipopolysaccharide (LPS) or saline as control. After delivery at 113 days GA, the cyto-architecture of the cingulate cortex (CC) was examined by immunohistochemistry. High dose LPS exposure resulted in a decreased density of GFAP-, calbindin D-28K- and parvalbumin-immunoreactive cells in the CC. In addition, these cells and calretinin-immunoreactive cells showed a changed morphology with reduced cell processes. This study provides further evidence that intra-uterine endotoxemia can induce changes in the fetal brain which correspond with changes seen in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 39 | J. Neurosci. 2012 Aug 32: 10841-53 |
| PMID | 22875919 |
| Title | Schizophrenia-like features in transgenic mice overexpressing human HO-1 in the astrocytic compartment. |
| Abstract | Delineation of key molecules that act epigenetically to transduce diverse stressors into established patterns of disease would facilitate the advent of preventive and disease-modifying therapeutics for a host of neurological disorders. Herein, we demonstrate that selective overexpression of the stress protein heme oxygenase-1 (HO-1) in astrocytes of novel GFAP.HMOX1 transgenic mice results in subcortical oxidative stress and mitochondrial damage/autophagy; diminished neuronal reelin content (males); induction of Nurr1 and Pitx3 with attendant suppression of their targeting miRNAs, 145 and 133b; increased tyrosine hydroxylase and ?-synuclein expression with downregulation of the targeting miR-7b of the latter; augmented dopamine and serotonin levels in basal ganglia; reduced D1 receptor binding in nucleus accumbens; axodendritic pathology and altered hippocampal cytoarchitectonics; impaired neurovascular coupling; attenuated prepulse inhibition (males); and hyperkinetic behavior. The GFAP.HMOX1 neurophenotype bears resemblances to human schizophrenia and other neurodevelopmental conditions and implicates glial HO-1 as a prime transducer of inimical (endogenous and environmental) influences on the development of monoaminergic circuitry. Containment of the glial HO-1 response to noxious stimuli at strategic points of the life cycle may afford novel opportunities for the effective management of human neurodevelopmental and neurodegenerative conditions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 40 | J Proteomics 2013 Oct 91: 556-68 |
| PMID | 24007662 |
| Title | Quantitative clinical proteomic study of autopsied human infarcted brain specimens to elucidate the deregulated pathways in ischemic stroke pathology. |
| Abstract | Ischemic stroke, still lacking an effective neuroprotective therapy is the third leading cause of global mortality and morbidity. Here, we have applied an 8-plex iTRAQ-based 2D-LC-MS/MS strategy to study the commonly regulated infarct proteome from three different brain regions (putamen, thalamus and the parietal lobe) of female Japanese patients. Infarcts were compared with age-, post-mortem interval- and location-matched control specimens. The iTRAQ experiment confidently identified 1520 proteins with 0.1% false discovery rate. Bioinformatics data mining and immunochemical validation of pivotal perturbed proteins revealed a global failure of the cellular energy metabolism in the infarcted tissues as seen by the parallel down-regulation of proteins related to glycolysis, pyruvate dehydrogenase complex, TCA cycle and oxidative phosphorylation. The concomitant down-regulation of all participating proteins (SLC25A11, SLC25A12, GOT2 and MDH2) of malate-aspartate shuttle might be responsible for the metabolic in-coordination between the cytosol and mitochondria resulting in the failure of energy metabolism. The levels of proteins related to reactive gliosis (VIM, GFAP) and anti-inflammatory response (ANXA1, ANXA2) showed an increasing trend. The elevation of ferritin (FTL, FTH1) may indicate an iron-mediated oxidative imbalance aggravating the mitochondrial failure and neurotoxicity. The deregulated proteins could be useful as potential therapeutic targets or biomarkers for ischemic stroke. Clinical proteomics of stroke has been lagging behind other areas of clinical proteomics like Alzheimer's disease or schizophrenia. Our study is the first quantitative clinical proteomics study where iTRAQ-2D-LC-MS/MS has been utilized in the area of ischemic stroke to obtain a comparative profile of human ischemic infarcts and age-, sex-, location- and post-mortem interval-matched control brain specimens. Different pathological attributes of ischemic stroke well-known through basic and pre-clinical research such as failure of cellular energy metabolism, reactive gliosis, activation of anti-inflammatory response and aberrant iron metabolism have been observed at the bedside. Our dataset could act as a reference for similar studies done in the future using ischemic brain samples from various brain banks across the world. A meta-analysis of these studies could help to map the pathological proteome specific to ischemic stroke that will guide the scientific community to better evaluate the pros and cons of the pre-clinical models for efficacy and mechanistic studies. Infarct being the core of injury should have the most intense regulation for several key proteins involved in the pathophysiology of ischemic stroke. Hence, a part of the up-regulated proteome could leak into the general circulation that may offer candidates of interest as potential biomarkers. In support of our proposed hypothesis, we report ferritin in the current study as one of the most elevated proteins in the infarct, which has been documented as a biomarker in the context of ischemic stroke by an independent study. Overall, our approach has the potential to identify probable therapeutic targets and biomarkers in the area of ischemic stroke. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 41 | Exp. Eye Res. 2013 Nov 116: 1-8 |
| PMID | 23954924 |
| Title | Developmental expression of dysbindin in Muller cells of rat retina. |
| Abstract | Dysbindin, the product of the DTNBP1 gene, was identified by yeast two hybrid assay as a binding partner of dystrobrevin, a cytosolic component of the dystrophin protein complex. Although its functional role has not yet been completely elucidated, the finding that dysbindin assembles into the biogenesis of lysosome related organelles complex 1 (BLOC-1) suggests that it participates in intracellular trafficking and biogenesis of organelles and vesicles. Dysbindin is ubiquitous and in brain is expressed primarily in neurons. Variations at the dysbindin gene have been associated with increased risk for schizophrenia. As anomalies in retinal function have been reported in patients suffering from neuropsychiatric disorders, we investigated the expression of dysbindin in the retina. Our results show that differentially regulated dysbindin isoforms are expressed in rat retina during postnatal maturation. Interestingly, we found that dysbindin is mainly localized in Müller cells. The identification of dysbindin in glial cells may open new perspectives for a better understanding of the functional involvement of this protein in visual alterations associated to neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 42 | Neuropharmacology 2013 May 68: 223-31 |
| PMID | 22939999 |
| Title | Maternal deprivation effects on brain plasticity and recognition memory in adolescent male and female rats. |
| Abstract | Data from both human and animal studies suggest that exposure to stressful life events at neonatal stages may increase the risk of psychopathology at adulthood. In particular, early maternal deprivation, 24 h at postnatal day (pnd) 9, has been associated with persistent neurobehavioural changes similar to those present in developmental psychopathologies such as depression and schizophrenic-related disorders. Most neuropsychiatric disorders first appear during adolescence, however, the effects of MD on adolescent animals' brain and behaviour have been scarcely explored. In the present study, we aimed to investigate the emotional and cognitive consequences of MD in adolescent male and female rats, as well as possible underlying neurobiological mechanisms within frontal cortex and hippocampus. Animals were exposed to a battery of behavioural tasks, from pnd 35 to 42, to evaluate cognitive [spontaneous alternation task (SAT) and novel object test (NOT)] and anxiety-related responses [elevated plus maze (EPM)] during adolescence. Changes in neuronal and glial cells, alterations in synaptic plasticity as well as modifications in cannabinoid receptor expression were investigated in a parallel group of control and adolescent (pnd 40) male and female animals. Notably, MD induced a significant impairment in recognition memory exclusively among females. A generalized decrease in NeuN expression was found in MD animals, together with an increase in hippocampal glial fibrillar acidic protein (GFAP) expression exclusively among MD adolescent males. In addition, MD induced in the frontal cortex and hippocampus of male and female adolescent rats a significant reduction in brain derived neurotrophic factor (BDNF) and postsynaptic density (PSD95) levels, together with a decrease in synaptophysin in frontal cortex and neural cell adhesion molecule (NCAM) in hippocampus. MD induced, in animals of both sexes, a significant reduction in CB1R expression, but an increase in CB2R that was statistically significant only for the frontal cortex. Taken together, these results indicate that adolescent females are more vulnerable than males to the cognitive deficits derived from MD despite the changes in neural cells, cannabinoid receptors, as well as the reduction in neural plasticity seem to be similar in both sexes. Further investigation is needed to understand the neurobiological mechanisms underlying the sexual dimorphisms associated to the MD effects, and thus, for a better understanding of the specific sex-dependent vulnerabilities to early life stress. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 43 | Behav. Brain Res. 2013 Apr 242: 178-90 |
| PMID | 23291154 |
| Title | Chronic administration of risperidone in a rat model of schizophrenia: a behavioural, morphological and molecular study. |
| Abstract | In the present work we analyzed the effect of the chronic administration of risperidone (2mg/kg over 65 days) on behavioural, morphological and molecular aspects in an experimental model of schizophrenia obtained by bilateral injection of ibotenic acid into the ventral hippocampus of new-born rats. Our results show that during their adult lives the animals with hippocampal lesions exhibit different alterations, mainly at behavioural level and in the gene expression of dopamine D(2) and 5-HT(2A) receptors. However, at morphological level the study performed on the prefrontal cortex did not reveal any alterations in either the thickness or the number of cells immunoreactive for c-Fos, GFAP, CBP or PV. Overall, risperidone administration elicited a trend towards the recovery of the values previously altered by the hippocampal lesion, approaching the values seen in the animals without lesions. It may be concluded that the administration of risperidone in the schizophrenia model employed helps to improve the altered functions, with no significant negative effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 44 | Neurobiol. Dis. 2013 Nov 59: 63-8 |
| PMID | 23867234 |
| Title | Cuprizone short-term exposure: astrocytic IL-6 activation and behavioral changes relevant to psychosis. |
| Abstract | A growing body of evidence suggests the involvement of inflammatory processes in the pathophysiology of schizophrenia. Four- to 8-week exposure to cuprizone, a copper chelator, causes robust demyelination and has been used to build a model for multiple sclerosis. In contrast, we report here the effects of 1-week cuprizone exposure in mice. This short-term cuprizone exposure elicits behavioral changes that include augmented responsiveness to methamphetamine and phencyclidine, as well as impaired working memory. The cellular effects of 1-week cuprizone exposure differ substantially from the longer-term exposure; perturbation of astrocytes and microglia is induced without any sign of demyelination. Furthermore, the proinflammatory cytokine interleukin-6 was significantly up-regulated in glial fibrillary acidic protein (GFAP)-positive cells. We propose that this cuprizone short-term exposure may offer a model to study some aspects of biology relevant to schizophrenia and related conditions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 45 | Eur Arch Psychiatry Clin Neurosci 2013 Feb 263: 41-52 |
| PMID | 22660922 |
| Title | Astrocyte decrease in the subgenual cingulate and callosal genu in schizophrenia. |
| Abstract | Decreases in glial cell density and in GFAP mRNA in the anterior cingulate cortex have been reported in schizophrenia, bipolar disorder and major depressive disorder. Our study examines astrocyte and oligodendrocyte density in the white and grey matter of the subgenual cingulate cortex, and at the midline of the genu of the corpus callosum, in schizophrenia, bipolar disorder, depression and normal control cases. Serial coronal sections were stained with H and E for anatomical guidance, cresyl haematoxylin for oligodendrocyte identification and GFAP immunohistochemistry for astrocyte identification. Oligodendrocyte and astrocyte density was measured using systematic anatomical distinctions and randomised counting methods. A significant decrease in astrocyte density was observed in schizophrenia compared with normal controls in the cingulate grey matter, cingulate white matter and the midline of the corpus callosum (p = 0.025). Bipolar disorder and depression cases showed no significant changes in astrocyte density. Oligodendrocytes did not show any changes between diagnostic groups. In subgenual cingulate cortex, the ratio of oligodendrocytes to astrocytes was decreased between the controls and the three disease groups, suggesting a specific glial cell type specific change in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 46 | Schizophr. Res. 2013 Jun 147: 24-31 |
| PMID | 23566496 |
| Title | Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in the postmortem frontal cortex from schizophrenia patients. |
| Abstract | schizophrenia (SZ) is a progressive, neuropsychiatric disorder associated with cognitive impairment. A number of brain alterations have been linked to cognitive impairment, including neuroinflammation, excitotoxicity, increased arachidonic acid (AA) signaling and reduced synaptic protein. On this basis, we tested the hypothesis that SZ pathology is associated with these pathological brain changes. To do this, we examined postmortem frontal cortex from 10 SZ patients and 10 controls and measured protein and mRNA levels of cytokines, and astroglial, microglial, neuroinflammatory, excitotoxic, AA cascade, apoptotic and synaptic markers. Mean protein and mRNA levels of interleukin-1?, tumor necrosis factor-?, glial acidic fibrillary protein (GFAP), a microglial marker CD11b, and nuclear factor kappa B subunits were significantly increased in SZ compared with control brain. Protein and mRNA levels of cytosolic and secretory phospholipase A2 and cyclooxygenase also were significantly elevated. N-methyl-d-aspartate receptor subunits 1 and 2B, inducible nitric oxide synthase and c-Fos were not significantly different. In addition, reduced protein and mRNA levels of brain-derived neurotrophic factor, synaptophysin and drebrin were found in SZ compared with control frontal cortex. Increased neuroinflammation and AA cascade enzyme markers with synaptic protein loss could promote disease progression and cognitive defects in SZ patients. Drugs that downregulate these changes might be considered for new therapies in SZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 47 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Oct -1: -1 |
| PMID | 24513021 |
| Title | Increased Stability of Microtubules in Cultured Olfactory Neuroepithelial Cells from Individuals with Schizophrenia. |
| Abstract | Microtubules (MTs) are essential components of the cytoskeleton that play critical roles in neurodevelopment and adaptive central nervous system functioning. MTs are essential to growth cone advance and ultrastructural events integral to synaptic plasticity; these functions figure significantly into current pathophysiologic conceptualizations of schizophrenia. To date, no study has directly investigated MT dynamics in humans with schizophrenia. We therefore compared the stability of MTs in olfactory neuroepithelial (OE) cells between schizophrenia cases and matched nonpsychiatric comparison subjects. For this purpose, we applied nocodazole (Nz) to cultured OE cells obtained from tissue biopsies from seven living schizophrenia patients and seven matched comparison subjects; all schizophrenia cases were on antipsychotic medications. Nz allows MT depolymerization to be followed but prevents repolymerization, so that in living cells treated for varying time intervals, the MTs that are stable for a given treatment interval remain. Our readout of MT stability was the time at which fewer than 10 MTs per cell could be distinguished by anti-?-tubulin immunofluorescence. The percentage of cells with >10 intact MTs at specified intervals following Nz treatment was estimated by systematic uniform random sampling with Visiopharm software. These analyses showed that the mean percentages of OE cells with intact MTs were significantly greater for schizophrenia cases than for the matched comparison subjects at 10, 15, and 30minutes following Nz treatment indicating increased MT stability in OE cells from schizophrenia patients (p=.0007 at 10minutes; p=.0008 at 15minutes; p=.036 at 30minutes). In conclusion, we have demonstrated increased MT stability in nearly all cultures of OE cells from individuals with schizophrenia who received several antipsychotic treatments, versus comparison subjects matched for age and sex. While we cannot rule out a possible confounding effect of antipsychotic medications, these findings may reflect analogous neurobiological events in at least a subset of immature neurons or other cell types during gestation, or newly generated cells destined for the olfactory bulb or hippocampus, suggesting a mechanism that underlies findings of postmortem and neuroimaging investigations of schizophrenia. Future studies aimed at replicating these findings, including samples of medication-naïve subjects with schizophrenia, and reconciling the results with other studies, will be necessary. Although the observed abnormalities may suggest one of a number of putative pathophysiologic anomalies in schizophrenia, this work may ultimately have implications for an improved understanding of pathogenic processes related to this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 48 | Schizophr. Res. 2013 Oct 150: 252-7 |
| PMID | 23911257 |
| Title | Increased expression of glial fibrillary acidic protein in prefrontal cortex in psychotic illness. |
| Abstract | Astrocyte dysregulation has been implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BPD), however the exact nature of astrocytic alterations remains to be identified. In this study we investigated whether levels of four astrocyte-specific proteins; glial fibrillary acidic protein (GFAP), aldehyde dehydrogenase 1L1 (ALDH1L1), vimentin and excitatory amino acid transporter 1 (EAAT1) are altered in SCZ and BPD. Relative concentrations of GFAP, ALDH1L1, vimentin and EAAT1 were assessed post-mortem in dorsolateral prefrontal cortex in SCZ (n=35), BPD (n=34) and non-psychiatric controls (n=35) by western blotting. The same proteins were also quantified in cingulate cortex of rats administered the antipsychotics haloperidol and clozapine. Elevated levels of GFAP were observed in SCZ and BPD, when compared to controls. GFAP was also significantly increased when comparing individuals with psychotic symptoms against those without. Vimentin, ALDH1L1 and EAAT1 levels did not differ between groups. Rats exposed to antipsychotics did not exhibit significant differences in any astrocytic protein, suggesting that increased GFAP in SCZ is not attributable to antipsychotic treatment. Our findings indicate that astrocyte pathology may be associated with psychotic symptoms. Lack of ALDH1L1 and vimentin variability and increased GFAP levels may imply that astrocyte numbers are unchanged but astrocytes are partially activated, or may indicate a specific dysregulation of GFAP. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 49 | PLoS ONE 2013 -1 8: e59685 |
| PMID | 23536886 |
| Title | Functional impacts of NRXN1 knockdown on neurodevelopment in stem cell models. |
| Abstract | Exonic deletions in NRXN1 have been associated with several neurodevelopmental disorders, including autism, schizophrenia and developmental delay. However, the molecular mechanism by which NRXN1 deletions impact neurodevelopment remains unclear. Here we used human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) as models to investigate the functional impacts of NRXN1 knockdown. We first generated hiPSCs from skin fibroblasts and differentiated them into neural stem cells (NSCs). We reduced NRXN1 expression in NSCs via a controlled shRNAmir-based knockdown system during differentiation, and monitored the transcriptome alteration by RNA-Seq and quantitative PCR at several time points. Interestingly, half reduction of NRXN1 expression resulted in changes of expression levels for the cell adhesion pathway (20 genes, P?=?2.8×10(-6)) and neuron differentiation pathway (13 genes, P?=?2.1×10(-4)), implicating that single-gene perturbation can impact biological networks important for neurodevelopment. Furthermore, astrocyte marker GFAP was significantly reduced in a time dependent manner that correlated with NRXN1 reduction. This observation was reproduced in both hiPSCs and hESCs. In summary, based on in vitro models, NRXN1 deletions impact several biological processes during neurodevelopment, including synaptic adhesion and neuron differentiation. Our study highlights the utility of stem cell models in understanding the functional roles of copy number variations (CNVs) in conferring susceptibility to neurodevelopmental diseases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 50 | Neuropsychopharmacology 2013 Jul 38: 1409-25 |
| PMID | 23389689 |
| Title | Deficiency of schnurri-2, an MHC enhancer binding protein, induces mild chronic inflammation in the brain and confers molecular, neuronal, and behavioral phenotypes related to schizophrenia. |
| Abstract | Schnurri-2 (Shn-2), an nuclear factor-?B site-binding protein, tightly binds to the enhancers of major histocompatibility complex class I genes and inflammatory cytokines, which have been shown to harbor common variant single-nucleotide polymorphisms associated with schizophrenia. Although genes related to immunity are implicated in schizophrenia, there has been no study showing that their mutation or knockout (KO) results in schizophrenia. Here, we show that Shn-2 KO mice have behavioral abnormalities that resemble those of schizophrenics. The mutant brain demonstrated multiple schizophrenia-related phenotypes, including transcriptome/proteome changes similar to those of postmortem schizophrenia patients, decreased parvalbumin and GAD67 levels, increased theta power on electroencephalograms, and a thinner cortex. Dentate gyrus granule cells failed to mature in mutants, a previously proposed endophenotype of schizophrenia. Shn-2 KO mice also exhibited mild chronic inflammation of the brain, as evidenced by increased inflammation markers (including GFAP and NADH/NADPH oxidase p22 phox), and genome-wide gene expression patterns similar to various inflammatory conditions. Chronic administration of anti-inflammatory drugs reduced hippocampal GFAP expression, and reversed deficits in working memory and nest-building behaviors in Shn-2 KO mice. These results suggest that genetically induced changes in immune system can be a predisposing factor in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 51 | Neuropsychopharmacology 2013 Jul 38: 1409-25 |
| PMID | 23389689 |
| Title | Deficiency of schnurri-2, an MHC enhancer binding protein, induces mild chronic inflammation in the brain and confers molecular, neuronal, and behavioral phenotypes related to schizophrenia. |
| Abstract | Schnurri-2 (Shn-2), an nuclear factor-?B site-binding protein, tightly binds to the enhancers of major histocompatibility complex class I genes and inflammatory cytokines, which have been shown to harbor common variant single-nucleotide polymorphisms associated with schizophrenia. Although genes related to immunity are implicated in schizophrenia, there has been no study showing that their mutation or knockout (KO) results in schizophrenia. Here, we show that Shn-2 KO mice have behavioral abnormalities that resemble those of schizophrenics. The mutant brain demonstrated multiple schizophrenia-related phenotypes, including transcriptome/proteome changes similar to those of postmortem schizophrenia patients, decreased parvalbumin and GAD67 levels, increased theta power on electroencephalograms, and a thinner cortex. Dentate gyrus granule cells failed to mature in mutants, a previously proposed endophenotype of schizophrenia. Shn-2 KO mice also exhibited mild chronic inflammation of the brain, as evidenced by increased inflammation markers (including GFAP and NADH/NADPH oxidase p22 phox), and genome-wide gene expression patterns similar to various inflammatory conditions. Chronic administration of anti-inflammatory drugs reduced hippocampal GFAP expression, and reversed deficits in working memory and nest-building behaviors in Shn-2 KO mice. These results suggest that genetically induced changes in immune system can be a predisposing factor in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 52 | Hum. Mol. Genet. 2013 Apr 22: 1373-82 |
| PMID | 23321059 |
| Title | RNA-binding protein QKI regulates Glial fibrillary acidic protein expression in human astrocytes. |
| Abstract | Linkage, association and expression studies previously pointed to the human QKI, KH domain containing, RNA-binding (QKI) as a candidate gene for schizophrenia. Functional studies of the mouse orthologue Qk focused mainly on its role in oligodendrocyte development and myelination, while its function in astroglia remained unexplored. Here, we show that QKI is highly expressed in human primary astrocytes and that its splice forms encode proteins targeting different subcellular localizations. Uncovering the role of QKI in astrocytes is of interest in light of growing evidence implicating astrocyte dysfunction in the pathogenesis of several disorders of the central nervous system. We selectively silenced QKI splice variants in human primary astrocytes and used RNA sequencing to identify differential expression and splice variant composition at the genome-wide level. We found that an mRNA expression of Glial fibrillary acidic protein (GFAP), encoding a major component of astrocyte intermediate filaments, was down-regulated after QKI7 splice variant silencing. Moreover, we identified a potential QKI-binding site within the 3' untranslated region of human GFAP. This sequence was not conserved between mice and humans, raising the possibility that GFAP is a target for QKI in humans but not rodents. Haloperidol treatment of primary astrocytes resulted in coordinated increases in QKI7 and GFAP expression. Taken together, our results provide the first link between QKI and GFAP, two genes with alterations previously observed independently in schizophrenic patients. Our findings for QKI, together with its well-known role in myelination, suggest that QKI is a hub regulator of glia function in humans. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 53 | Hum. Mol. Genet. 2013 Apr 22: 1373-82 |
| PMID | 23321059 |
| Title | RNA-binding protein QKI regulates Glial fibrillary acidic protein expression in human astrocytes. |
| Abstract | Linkage, association and expression studies previously pointed to the human QKI, KH domain containing, RNA-binding (QKI) as a candidate gene for schizophrenia. Functional studies of the mouse orthologue Qk focused mainly on its role in oligodendrocyte development and myelination, while its function in astroglia remained unexplored. Here, we show that QKI is highly expressed in human primary astrocytes and that its splice forms encode proteins targeting different subcellular localizations. Uncovering the role of QKI in astrocytes is of interest in light of growing evidence implicating astrocyte dysfunction in the pathogenesis of several disorders of the central nervous system. We selectively silenced QKI splice variants in human primary astrocytes and used RNA sequencing to identify differential expression and splice variant composition at the genome-wide level. We found that an mRNA expression of Glial fibrillary acidic protein (GFAP), encoding a major component of astrocyte intermediate filaments, was down-regulated after QKI7 splice variant silencing. Moreover, we identified a potential QKI-binding site within the 3' untranslated region of human GFAP. This sequence was not conserved between mice and humans, raising the possibility that GFAP is a target for QKI in humans but not rodents. Haloperidol treatment of primary astrocytes resulted in coordinated increases in QKI7 and GFAP expression. Taken together, our results provide the first link between QKI and GFAP, two genes with alterations previously observed independently in schizophrenic patients. Our findings for QKI, together with its well-known role in myelination, suggest that QKI is a hub regulator of glia function in humans. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 54 | J Clin Psychiatry 2014 Aug 75: e794-801 |
| PMID | 25191916 |
| Title | Combining serum protein concentrations to diagnose schizophrenia: a preliminary exploration. |
| Abstract | It is difficult for clinicians to diagnose schizophrenia solely based on interviews. We explored the diagnostic efficiency and predictive capability of serum biomarkers for schizophrenia. Levels of ? nerve growth factor (?-NGF), brain-derived neurotrophic factor (BDNF), interleukin 6 (IL-6), tumor necrosis factor ? (TNF-?), interferon ? (IFN-?), calcium binding protein S100?, myelin basic protein (MBP), and glial fibrillary acidic protein (GFAP) were measured in the sera of 278 schizophrenia patients, 240 depression and bipolar disorder patients, and 260 healthy controls. DSM-IV-TR criteria were used as the diagnostic criteria for schizophrenia and depressive and bipolar disorders. The diagnostic efficiency was high in patients with schizophrenia compared with the healthy controls. Receiver operating characteristic (ROC) curve analysis was used to ascertain the diagnostic efficiency of the 8 proteins. Data were collected between July 2010 and December 2012. One-way analysis of variance significantly demonstrated lower serum BDNF, MBP, and GFAP levels (F = 16.504, P < .001; F = 207.209, P < .001; F = 33.668, P < .001, respectively) but higher serum IL-6 and S100? concentrations (F = 15.250, P < .001; F = 12.751, P < .001, respectively) among patients with schizophrenia. ROC analysis of the discriminant scores of the serum ?-NGF, BDNF, IL-6, S100?, MBP, and GFAP levels resulted in significant discrimination between the schizophrenia and control groups (AUC = 0.922) and the depressive/bipolar disorder and control groups (AUC = 0.762). Serum levels of 6 proteins (but not TNF-? and IFN-?) contribute most to the diagnosis of schizophrenia. These proteins may prove to be useful adjuncts for the clinical assessment of this disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 55 | Front Synaptic Neurosci 2014 -1 6: 11 |
| PMID | 24822045 |
| Title | D-amino acid oxidase is expressed in the ventral tegmental area and modulates cortical dopamine. |
| Abstract | D-amino acid oxidase (DAO, DAAO) degrades the NMDA receptor co-agonist D-serine, modulating D-serine levels and thence NMDA receptor function. DAO inhibitors are under development as a therapy for schizophrenia, a disorder involving both NMDA receptor and dopaminergic dysfunction. However, a direct role for DAO in dopamine regulation has not been demonstrated. Here, we address this question in two ways. First, using in situ hybridization and immunohistochemistry, we show that DAO mRNA and immunoreactivity are present in the ventral tegmental area (VTA) of the rat, in tyrosine hydroxylase (TH)-positive and -negative neurons, and in glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes. Second, we show that injection into the VTA of sodium benzoate, a DAO inhibitor, increases frontal cortex extracellular dopamine, as measured by in vivo microdialysis and high performance liquid chromatography. Combining sodium benzoate and D-serine did not enhance this effect, and injection of D-serine alone affected dopamine metabolites but not dopamine. These data show that DAO is expressed in the VTA, and suggest that it impacts on the mesocortical dopamine system. The mechanism by which the observed effects occur, and the implications of these findings for schizophrenia therapy, require further study. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 56 | Front Synaptic Neurosci 2014 -1 6: 14 |
| PMID | 24959138 |
| Title | Activity of D-amino acid oxidase is widespread in the human central nervous system. |
| Abstract | It has been proposed that D-amino acid oxidase (DAO) plays an essential role in degrading D-serine, an endogenous coagonist of N-methyl-D-aspartate (NMDA) glutamate receptors. DAO shows genetic association with amyotrophic lateral sclerosis (ALS) and schizophrenia, in whose pathophysiology aberrant metabolism of D-serine is implicated. Although the pathology of both essentially involves the forebrain, in rodents, enzymatic activity of DAO is hindbrain-shifted and absent in the region. Here, we show activity-based distribution of DAO in the central nervous system (CNS) of humans compared with that of mice. DAO activity in humans was generally higher than that in mice. In the human forebrain, DAO activity was distributed in the subcortical white matter and the posterior limb of internal capsule, while it was almost undetectable in those areas in mice. In the lower brain centers, DAO activity was detected in the gray and white matters in a coordinated fashion in both humans and mice. In humans, DAO activity was prominent along the corticospinal tract, rubrospinal tract, nigrostriatal system, ponto-/olivo-cerebellar fibers, and in the anterolateral system. In contrast, in mice, the reticulospinal tract and ponto-/olivo-cerebellar fibers were the major pathways showing strong DAO activity. In the human corticospinal tract, activity-based staining of DAO did not merge with a motoneuronal marker, but colocalized mostly with excitatory amino acid transporter 2 and in part with GFAP, suggesting that DAO activity-positive cells are astrocytes seen mainly in the motor pathway. These findings establish the distribution of DAO activity in cerebral white matter and the motor system in humans, providing evidence to support the involvement of DAO in schizophrenia and ALS. Our results raise further questions about the regulation of D-serine in DAO-rich regions as well as the physiological/pathological roles of DAO in white matter astrocytes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 57 | J Neuroinflammation 2014 -1 11: 128 |
| PMID | 25069615 |
| Title | Cytokine pathway disruption in a mouse model of schizophrenia induced by Munc18-1a overexpression in the brain. |
| Abstract | An accumulating body of evidence points to the significance of neuroinflammation and immunogenetics in schizophrenia, and an imbalance of cytokines in the central nervous system (CNS) has been suggested to be associated with the disorder. Munc18-overexpressing mice (Munc18-OE) have provided a model for the study of the alterations that may underlie the symptoms of subjects with schizophrenia. The aim of the present study was to elucidate the involvement of neuroinflammation and cytokine imbalance in this model. Cytokines were evaluated in the cortex and the striatum of Munc18-OE and wild-type (WT) mice by enzyme-linked immunosorbent assay (ELISA). Protein levels of specific microglia and macrophage, astrocytic and neuroinflammation markers were quantified by western blot in the cortex and the striatum of Munc18-OE and WT mice. Each cytokine evaluated (Interferon-gamma (IFN-?), Tumor Necrosis Factor-alpha (TNF-?), Interleukin-2 (IL-2) and CCL2 chemokine) was present at higher levels in the striatum of Munc18-OE mice than WT. Cortical TNF-? and IL-2 levels were significantly lower in Munc18-OE mice than WT mice. The microglia and macrophage marker CD11b was lower in the cortexes of Munc18-OE mice than WT, but no differences were observed in the striatum. Glial Fibrillary Acidic Protein (GFAP) and Nuclear Factor-kappaB (NF-?B)p65 levels were not different between the groups. Interleukin-1beta (IL-1?) and IL-6 levels were beneath detection limits. The disrupted levels of cytokines detected in the brain of Munc18-OE mice was found to be similar to clinical reports and endorses study of this type for analysis of this aspect of the disorder. The lower CD11b expression in the cortex but not in the striatum of the Munc18-OE mice may reflect differences in physiological activity. The cytokine expression pattern observed in Munc18-OE mice is similar to a previously published model of schizophrenia caused by maternal immune activation. Together, these data suggest a possible role for an immune imbalance in this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 58 | J Psychiatry Neurosci 2014 Nov 39: 376-85 |
| PMID | 24936776 |
| Title | Evidence for morphological alterations in prefrontal white matter glia in schizophrenia and bipolar disorder. |
| Abstract | Brain imaging studies suggest that volume reductions and compromised white matter integrity occur in schizophrenia and bipolar disorder (BD). However, the cellular correlates have not yet been identified. To address this issue we assessed oligodendrocyte, astrocyte and microglial populations in postmortem white matter from schizophrenia, BD and nonpsychiatric control samples. The density, areal fraction and spatial distribution of glial fibrillary acidic protein (GFAP)-expressing astrocytes and ionized calcium-binding adaptor molecule-1 (IBA-1)-expressing microglia as well as the density, nuclear size and spatial distribution of Nissl-stained oligodendrocytes were quantified in postmortem white matter adjacent to the dorsolateral prefrontal cortex (Brodmann area 9) in schizophrenia, BD and control samples (n = 20). In addition, the oligodendrocyte-associated proteins myelin basic protein and 2,3-cyclic-nucleotide 3-phosphodiesterase (CNPase) were quantified in the same samples by enzyme-linked immunosorbent assay and immunoblotting. Oligodendrocyte density (p = 0.012) and CNPase protein levels (p = 0.038) differed between groups, being increased in BD compared with control samples. The GFAP area fraction (p = 0.05) and astrocyte spatial distribution (p = 0.040) also differed between groups, reflecting decreased area fraction and increased cell clustering in both schizophrenia and BD samples. Oligodendrocytes were identified using morphological criteria. This study provides evidence for glial pathology in prefrontal white matter in schizophrenia and BD. Changes in oligodendrocyte and astrocyte populations in white matter in the major psychiatric disorders may reflect disruptions in structural or metabolic support of axons. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 59 | Aust N Z J Psychiatry 2014 Aug 48: 722-34 |
| PMID | 24744400 |
| Title | Increased expression of astrocyte markers in schizophrenia: Association with neuroinflammation. |
| Abstract | While schizophrenia may have a progressive component, the evidence for neurodegenerative processes as indicated by reactive astrocytes is inconclusive. We recently identified a subgroup of individuals with schizophrenia with increased expression of inflammatory markers in prefrontal cortex, and hypothesized that this subgroup would also have reactive astrocytes. We measured glial fibrillary acidic protein (GFAP) mRNA by quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) and protein levels by immunoblotting in grey matter homogenate from 37 individuals with schizophrenia and 37 unaffected controls. We examined the morphology of GFAP-positive astrocytes in immunostained sections of middle frontal gyrus. We tested if GFAP expression or astrocyte morphology were altered in people with schizophrenia with increased expression of inflammatory markers. We used RNA-Seq data on a subset of patients and controls (n=20/group) to ascertain whether mRNA transcripts associated with astrogliosis were elevated in the individuals with active neuroinflammation. GFAP (mRNA and protein) levels and astrocyte morphology were not significantly different between people with schizophrenia and controls overall. However, individuals with schizophrenia with neuroinflammation had increased expression of GFAP mRNA (t(33)=2.978, p=0.005), hypertrophic astrocyte morphology (?(2)(2)=6.281, p=0.043), and statistically significant elevated expression of three mRNA transcripts previously associated with astrogliosis. We found clear evidence of astrogliosis in a subset of people with schizophrenia. We suggest that the lack of astrogliosis reported in previous studies may be due to cohort differences in aetiopathology, illness stage, treatment exposure, or a failure to examine subsets of people with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 60 | Eur Arch Psychiatry Clin Neurosci 2014 Jun 264: 357-62 |
| PMID | 24374936 |
| Title | Fibrillary astrocytes are decreased in the subgenual cingulate in schizophrenia. |
| Abstract | Decreases in astrocyte density and in glial fibrillary acid protein (GFAP) mRNA in the anterior cingulate cortex have been reported changed in mood and affective disorders. Our study examines the relative density and frequency of fibrillary and gemistocytic astrocytes in the white matter of the subgenual cingulate cortex in 11 schizophrenia, 16 bipolar disorder, 20 major depression and 20 normal control cases. Serial coronal sections were stained with H&E for anatomical guidance and GFAP immunohistochemistry for astrocyte identification. Astrocyte density was measured using systematic anatomical distinctions and randomised counting methods previously reported. Astrocytes were classified as fibrillary or gemistocytic based on staining and morphometric criteria and were measured in the crown and base of the gyral white matter. Fibrillary astrocytes were decreased in the base of the cingulate white matter in schizophrenia (p = 0.046), with no change in the density of gemistocytic astrocytes. There was no change in density of gemistocytic astrocytes. This suggests that the previously reported decrease in astrocytes in schizophrenia in the subgenual cingulate is accounted for only by a change in fibrillary astrocytes. With recent findings suggesting fibrillary astrocytes regulate synaptic glutamate this morphological change may relate to disregulation of function of the subgenual cingulate cortex. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 61 | J Neuroinflammation 2015 -1 12: 38 |
| PMID | 25889039 |
| Title | Mesial temporal lobe epilepsy with psychiatric comorbidities: a place for differential neuroinflammatory interplay. |
| Abstract | Despite the strong association between epilepsy and psychiatric comorbidities, few biological substrates are currently described. We have previously reported neuropathological alterations in mesial temporal lobe epilepsy (MTLE) patients with major depression and psychosis that suggest a morphological and neurochemical basis for psychopathological symptoms. Neuroinflammatory-related structures and molecules might be part of the altered neurochemical milieu underlying the association between epilepsy and psychiatric comorbidities, and such features have not been previously investigated in humans. MTLE hippocampi of subjects without psychiatric history (MTLEW), MTLE?+?major depression (MTLE?+?D), and MTLE?+?interictal psychosis (MTLE?+?P) derived from epilepsy surgery and control necropsies were investigated for reactive astrocytes (glial fibrillary acidic protein (GFAP)), activated microglia (human leukocyte antigen, MHC class II (HLA-DR)), glial metallothionein-I/II (MT-I/II), and aquaporin 4 (AQP4) immunohistochemistry. We found an increased GFAP immunoreactive area in the molecular layers, granule cell layer, and cornus ammonis region 2 (CA2) and cornus ammonis region 1 (CA1) of MTLEW and MTLE?+?P, respectively, compared to MTLE?+?D. HLA-DR immunoreactive area was higher in cornus ammonis region 3 (CA3) of MTLE?+?P, compared to MTLE?+?D and MTLEW, and in the hilus, when compared to MTLEW. MTLEW cases showed increased MT-I/II area in the granule cell layer and CA1, compared to MTLE?+?P, and in the parasubiculum, when compared to MTLE?+?D and MTLE?+?P. Differences between MTLE and control, such as astrogliosis, microgliosis, increased MT-I/II, and decreased perivascular AQP4 in the epileptogenic hippocampus, were in agreement to what is currently described in the literature. Neuroinflammatory-related molecules in MTLE hippocampus show a distinct pattern of expression when patients present with a comorbid psychiatric diagnosis, similar to what is found in the pure forms of schizophrenia and major depression. Future studies focusing on inflammatory characteristics of MTLE with psychiatric comorbidities might help in the design of better therapeutic strategies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 62 | PLoS ONE 2015 -1 10: e0145651 |
| PMID | 26700309 |
| Title | Reactive Transformation and Increased BDNF Signaling by Hippocampal Astrocytes in Response to MK-801. |
| Abstract | MK-801, also known as dizocilpine, is a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist that induces schizophrenia-like symptoms. While astrocytes have been implicated in the pathophysiology of psychiatric disorders, including schizophrenia, astrocytic responses to MK-801 and their significance to schizotypic symptoms are unclear. Changes in the expression levels of glial fibrillary acid protein (GFAP), a marker of astrocyte activation in response to a variety of pathogenic stimuli, were examined in the hippocampus of rats treated with the repeated MK-801 injection (0.5 mg/10 ml/kg body weight for 6 days) and in primary cultured hippocampal astrocytes incubated with MK-801 (5 or 20 ?M for 24 h). Moreover, the expression levels of BDNF and its receptors TrkB and p75 were examined in MK-801-treated astrocyte cultures. MK-801 treatment enhanced GFAP expression in the rat hippocampus and also increased the levels of GFAP protein and mRNA in hippocampal astrocytes in vitro. Treatment of cultured hippocampal astrocytes with MK-801 enhanced protein and mRNA levels of BDNF, TrkB, and p75. Collectively, our results suggest that hippocampal astrocytes may contribute to the pathophysiology of schizophrenia symptoms associated with NMDA receptor hypofunction by reactive transformation and altered BDNF signaling. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 63 | Front Cell Neurosci 2015 -1 9: 489 |
| PMID | 26733814 |
| Title | Changes in Astroglial Markers in a Maternal Immune Activation Model of Schizophrenia in Wistar Rats are Dependent on Sex. |
| Abstract | Data from epidemiological studies suggest that prenatal exposure to bacterial and viral infection is an important environmental risk factor for schizophrenia. The maternal immune activation (MIA) animal model is used to study how an insult directed at the maternal host can have adverse effects on the fetus, leading to behavioral and neurochemical changes later in life. We evaluated whether the administration of LPS to rat dams during late pregnancy affects astroglial markers (S100B and GFAP) of the offspring in later life. The frontal cortex and hippocampus were compared in male and female offspring on postnatal days (PND) 30 and 60. The S100B protein exhibited an age-dependent pattern of expression, being increased in the frontal cortex and hippocampus of the MIA group at PND 60, while at PND 30, male rats presented increased S100B levels only in the frontal cortex. Considering that S100B secretion is reduced by elevation of glutamate levels, we may hypothesize that this early increment in frontal cortex tissue of males is associated with elevated extracellular levels of glutamate and glutamatergic hypofunction, an alteration commonly associated with SCZ pathology. Moreover, we also found augmented GFAP in the frontal cortex of the LPS group at PND 30, but not in the hippocampus. Taken together data indicate that astroglial changes induced by MIA are dependent on sex and brain region and that these changes could reflect astroglial dysfunction. Such alterations may contribute to our understanding of the abnormal neuronal connectivity and developmental aspects of SCZ and other psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 64 | Schizophr. Res. 2015 Dec 169: 83-8 |
| PMID | 26545297 |
| Title | Changes in cholinergic and glutamatergic markers in the striatum from a sub-set of subjects with schizophrenia. |
| Abstract | Having separated a sub-group of people with schizophrenia based on a marked loss of cortical [(3)H]pirenzepine binding (MRDS); we wished to determine if MRDS had lower levels of [(3)H]pirenzepine and other muscarinic receptor antagonist binding to the striatum and if this was due to loss of pre- or post-synaptic neurons or glia measured using surrogate markers (25 kilodalton synaptosomal-associated protein (SNAP 25), postsynaptic density protein 95 (PSD 95), glial fibrillary acidic protein (GFAP) 41/43) of cell number. [(3)H]pirenzepine, [(3)H]AF-DX 384 and [(3)H]4-DAMP binding to the striatum from 37 subjects with schizophrenia (19 MRDS) and 20 controls as well as SNAP 25, PSD 95 and GFAP 41/43 in crude particulate membrane were measured. [(3)H]pirenzepine and [(3)H]AF-DX 384 binding to the striatum were significantly lower in schizophrenia due to lower binding of both radioligands in the striatum from MRDS. Levels of PSD 95 were higher in schizophrenia, predominantly due to higher levels in MRDS. Our data suggest muscarinic M1 ([(3)H]pirenzepine) and M2 and/or M4 receptors ([(3)H]AF-DX 384) are lower in the striatum from MRDS which could mediate inappropriate adaption to internal and external cues which, in turn, would affect motivation, cognition and motor control. Increased levels of PSD 95 could indicate increased post-synaptic boutons or changes in NMDA receptor-mediated signalling in MRDS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 65 | Neurol. Sci. 2015 Nov 36: 2027-33 |
| PMID | 26169757 |
| Title | LPA signaling is required for dopaminergic neuron development and is reduced through low expression of the LPA1 receptor in a 6-OHDA lesion model of Parkinson's disease. |
| Abstract | Lysophosphatidic acid (LPA) is a bioactive phospholipid that activates at least five known G-protein-coupled receptors (GPCRs): LPA1-LPA5. The nervous system is a major locus for LPA1 expression. LPA has been shown to regulate neuronal proliferation, migration, and differentiation during central nervous system development as well as neuronal survival. Furthermore, deficient LPA signaling has been implicated in several neurological disorders including neuropathic pain and schizophrenia. Parkinson's disease (PD) is a neurodegenerative movement disorder that results from the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). The specific molecular pathways that lead to DA neuron degeneration, however, are poorly understood. The influence of LPA in the differentiation of mesenchymal stem cells (MSCs) into DA neurons in vitro and LPA1 expression in a 6-hydroxydopamine (6-OHDA) lesion model of PD in vivo were examined in the present study. LPA induced neuronal differentiation in 80.2 % of the MSC population. These MSCs developed characteristic neuronal morphology and expressed the neuronal marker, neuron-specific enolase (NSE), while expression of the glial marker, glial fibrillary acidic protein (GFAP), was absent. Moreover, 27.6 % of differentiated MSCs were positive for tyrosine hydroxylase (TH), a marker for DA neurons. In the 6-OHDA PD rat model, LPA1 expression in the substantia nigra was significantly reduced compared to control. These results suggest LPA signaling via activation of LPA1 may be necessary for DA neuron development and survival. Furthermore, reduced LPA/LPA1 signaling may be involved in DA neuron degeneration thus contributing to the pathogenesis of PD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 66 | Schizophr. Res. 2015 May 164: 155-63 |
| PMID | 25680767 |
| Title | Decreased glial reactivity could be involved in the antipsychotic-like effect of cannabidiol. |
| Abstract | NMDA receptor hypofunction could be involved, in addition to the positive, also to the negative symptoms and cognitive deficits found in schizophrenia patients. An increasing number of data has linked schizophrenia with neuroinflammatory conditions and glial cells, such as microglia and astrocytes, have been related to the pathogenesis of schizophrenia. Cannabidiol (CBD), a major non-psychotomimetic constituent of Cannabis sativa with anti-inflammatory and neuroprotective properties induces antipsychotic-like effects. The present study evaluated if repeated treatment with CBD (30 and 60 mg/kg) would attenuate the behavioral and glial changes observed in an animal model of schizophrenia based on the NMDA receptor hypofunction (chronic administration of MK-801, an NMDA receptor antagonist, for 28 days). The behavioral alterations were evaluated in the social interaction and novel object recognition (NOR) tests. These tests have been widely used to study changes related to negative symptoms and cognitive deficits of schizophrenia, respectively. We also evaluated changes in NeuN (a neuronal marker), Iba-1 (a microglia marker) and GFAP (an astrocyte marker) expression in the medial prefrontal cortex (mPFC), dorsal striatum, nucleus accumbens core and shell, and dorsal hippocampus by immunohistochemistry. CBD effects were compared to those induced by the atypical antipsychotic clozapine. Repeated MK-801 administration impaired performance in the social interaction and NOR tests. It also increased the number of GFAP-positive astrocytes in the mPFC and the percentage of Iba-1-positive microglia cells with a reactive phenotype in the mPFC and dorsal hippocampus without changing the number of Iba-1-positive cells. No change in the number of NeuN-positive cells was observed. Both the behavioral disruptions and the changes in expression of glial markers induced by MK-801 treatment were attenuated by repeated treatment with CBD or clozapine. These data reinforces the proposal that CBD may induce antipsychotic-like effects. Although the possible mechanism of action of these effects is still unknown, it may involve CBD anti-inflammatory and neuroprotective properties. Furthermore, our data support the view that inhibition of microglial activation may improve schizophrenia symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 67 | Brain Behav. Immun. 2016 Apr -1: -1 |
| PMID | 27109609 |
| Title | Cerebral complement C1q activation in chronic Toxoplasma infection. |
| Abstract | Exposure to the neurotropic parasite, Toxoplasma gondii, causes significant brain and behavioral anomalies in humans and other mammals. Understanding the cellular mechanisms of T. gondii-generated brain pathologies would aid the advancement of novel strategies to reduce disease. Complement factor C1q is part of a classic immune pathway that functions peripherally to tag and remove infectious agents and cellular debris from circulation. In the developing and adult brain, C1q modifies neuronal architecture through synapse marking and pruning. T. gondii exposure and complement activation have both been implicated in the development of complex brain disorders such as schizophrenia. Thus, it seems logical that mechanistically, the physiological pathways associated with these two factors are connected. We employed a rodent model of chronic infection to investigate the extent to which cyst presence in the brain triggers activation of cerebral C1q. Compared to uninfected mice, cortical C1q was highly expressed at both the RNA and protein levels in infected animals bearing a high cyst burden. In these mice, C1q protein localized to cytoplasm, adjacent to GFAP-labeled astrocytes, near degenerating cysts, and in punctate patterns along processes. In summary, our results demonstrated an upregulation of cerebral C1q in response to latent T. gondii infection. Our data preliminarily suggest that this complement activity may aid in the clearance of this parasite from the CNS and in so doing, have consequences for the connectivity of neighboring cells and synapses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 68 | Neuroscience 2016 Jun 326: 105-16 |
| PMID | 27063100 |
| Title | Effects of enriched environment on alterations in the prefrontal cortex GFAP- and S100B-immunopositive astrocytes and behavioral deficits in MK-801-treated rats. |
| Abstract | A plethora of studies have indicated that enriched environment (EE) paradigm provokes plastic and morphological changes in astrocytes with accompanying increments of their density and positively affects the behavior of rodents. We also previously documented that EE could be employed to preclude several behavioral abnormalities, mainly cognitive deficits, attributed to postnatal N-methyl-d-aspartate (NMDA) receptor antagonist (MK-801) treatment, as a rodent model of schizophrenia (SCH) aspects. Given this, the current study quantitatively investigated the number of cells, presumed to be astrocytes, expressing two astroglia-associated proteins (S100B and glial fibrillary acidic protein (GFAP)) by immunohistochemistry in the prefrontal cortex (PFC), along with anxiety and passive avoidance (PA) learning behaviors by utilizing elevated plus maze (EPM) and shuttle-box tests, in MK-801-treated male wistar rats submitted to EE and non-EE rats. Following a treatment regime of sub-chronic MK-801 (1.0mg/kg i.p. daily for five consecutive days from postnatal day (P) 6), S-100B-positive cells and anxiety level were markedly increased, while the GFAP-positive cells and PA learning were notably attenuated. The trend of diminished GFAP-immunopositive cells and elevated S100B-immunostained cells in the PFC was reversed in the SCH-like rats by exposure of animals to EE, commencing from birth up to the time of experiments on P28-85. Additionally, EE exhibited an ameliorating effect on the behavioral abnormalities evoked by MK-801. Overall, present findings support that improper astrocyte functioning and behavioral changes, reminiscent of the many facets of SCH, occur consequential to repetitive administration of MK-801 and that raising rat pups in an EE mitigates these alterations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |