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Johann Steiner - One of the best experts on this subject based on the ideXlab platform.
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gabaergic system impairment in the hippocampus and superior temporal gyrus of patients with paranoid Schizophrenia a post mortem study
Schizophrenia Research, 2016Co-Authors: Johann Steiner, Hans-gert Bernstein, Henrik Dobrowolny, Ralf Brisch, Christian Mawrin, Katharina Braun, Zbigniew Jankowski, Kolja Schiltz, Marta Krzyzanowska, Andrea SchmittAbstract:Background: Glutamic acid decarboxylase (GAD) is a key enzyme in GABA synthesis and alterations in GABAergic neurotransmission related to glial abnormalities are thought to play a crucial role in the pathophysiology of Schizophrenia. This study aimed to identify potential differences regarding the neuropil expression of GAD between paranoid and Residual Schizophrenia. Methods: GAD65/67 immunostained histological sections were evaluated by quantitative densitometric analysis of GAD-immunoreactive (ir) neuropil. Regions of interest were the hippocampal formation (CA1 field and dentate gyrus [DG]), superior temporal gyrus (STG), and laterodorsal thalamic nucleus (LD). Data from 16 post-mortem Schizophrenia patient samples (10 paranoid and 6 Residual Schizophrenia cases) were compared with those from 16 matched controls. Results: Overall, Schizophrenia patients showed a lower GAD-ir neuropil density (P=0.014), particularly in the right CA1 (P = 0.033). However, the diagnostic subgroups differed significantly (P < 0.001), mainly because of lower right CA1 GAD-ir neuropil density in paranoid versus Residual patients (P = 0.036) and controls (P < 0.003). Significant GAD-ir neuropil reduction was also detected in the right STG layer V of paranoid versus Residual Schizophrenia cases (P = 0.042). GAD-ir neuropil density correlated positively with antipsychotic dosage, particularly in CA1 (right: r = 0.850, P = 0.004;left: r = 0.800, P = 0.010). Conclusion: Our finding of decreased relative density of GAD-ir neuropil suggests hypofunction of the GABAergic system, particularly in hippocampal CA1 field and STG layer V of patients with paranoid Schizophrenia. The finding that antipsychotic medication seems to counterbalance GABAergic hypofunction in Schizophrenia patients suggests the possibility of exploring new treatment avenues which target this system. (C) 2016 Elsevier B.V. All rights reserved.
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Increased density of DISC1-immunoreactive oligodendroglial cells in fronto-parietal white matter of patients with paranoid Schizophrenia
European Archives of Psychiatry and Clinical Neuroscience, 2016Co-Authors: Hans-gert Bernstein, Johann Steiner, Henrik Dobrowolny, Christian Mawrin, Esther Jauch, Bernhard BogertsAbstract:Profound white matter abnormalities have repeatedly been described in Schizophrenia, which involve the altered expression of numerous oligodendrocyte-associated genes. Transcripts of the disrupted-in-Schizophrenia 1 ( DISC1 ) gene, a key susceptibility factor in Schizophrenia, have recently been shown to be expressed by oligodendroglial cells and to negatively regulate oligodendrocyte differentiation and maturation. To learn more about the putative role(s) of oligodendroglia-associated DISC1 in Schizophrenia, we analyzed the density of DISC1-immunoreactive oligodendrocytes in the fronto-parietal white matter in postmortem brains of patients with Schizophrenia. Compared with controls ( N = 12) and cases with undifferentiated/Residual Schizophrenia ( N = 6), there was a significantly increased density of DISC1-expressing glial cells in paranoid Schizophrenia ( N = 12), which unlikely resulted from neuroleptic treatment. Pathophysiologically, over-expression of DISC1 protein(s) in white matter oligodendrocytes might add to the reduced levels of two myelin markers, 2′,3′-cyclic-nucleotide 3′-phosphodiesterase and myelin basic protein in Schizophrenia. Moreover, it might significantly contribute to cell cycle abnormalities as well as to deficits in oligodendroglial cell differentiation and maturation found in Schizophrenia.
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GABAergic system impairment in the hippocampus and superior temporal gyrus of patients with paranoid Schizophrenia: A post-mortem study.
Schizophrenia research, 2016Co-Authors: Johann Steiner, Hans-gert Bernstein, Henrik Dobrowolny, Ralf Brisch, Christian Mawrin, Marta Krzyżanowska, Katharina Braun, Zbigniew Jankowski, Kolja Schiltz, Andrea SchmittAbstract:Glutamic acid decarboxylase (GAD) is a key enzyme in GABA synthesis and alterations in GABAergic neurotransmission related to glial abnormalities are thought to play a crucial role in the pathophysiology of Schizophrenia. This study aimed to identify potential differences regarding the neuropil expression of GAD between paranoid and Residual Schizophrenia. GAD65/67 immunostained histological sections were evaluated by quantitative densitometric analysis of GAD-immunoreactive (ir) neuropil. Regions of interest were the hippocampal formation (CA1 field and dentate gyrus [DG]), superior temporal gyrus (STG), and laterodorsal thalamic nucleus (LD). Data from 16 post-mortem Schizophrenia patient samples (10 paranoid and 6 Residual Schizophrenia cases) were compared with those from 16 matched controls. Overall, Schizophrenia patients showed a lower GAD-ir neuropil density (P=0.014), particularly in the right CA1 (P=0.033). However, the diagnostic subgroups differed significantly (P<0.001), mainly because of lower right CA1 GAD-ir neuropil density in paranoid versus Residual patients (P=0.036) and controls (P<0.003). Significant GAD-ir neuropil reduction was also detected in the right STG layer V of paranoid versus Residual Schizophrenia cases (P=0.042). GAD-ir neuropil density correlated positively with antipsychotic dosage, particularly in CA1 (right: r=0.850, P=0.004; left: r=0.800, P=0.010). Our finding of decreased relative density of GAD-ir neuropil suggests hypofunction of the GABAergic system, particularly in hippocampal CA1 field and STG layer V of patients with paranoid Schizophrenia. The finding that antipsychotic medication seems to counterbalance GABAergic hypofunction in Schizophrenia patients suggests the possibility of exploring new treatment avenues which target this system. Copyright © 2016 Elsevier B.V. All rights reserved.
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Ribosomal DNA transcription in dorsal raphe nucleus neurons is increased in Residual Schizophrenia compared to depressed patients with affective disorders
Psychiatry research, 2015Co-Authors: Marta Krzyżanowska, Johann Steiner, Hans-gert Bernstein, Ralf Brisch, Christian Mawrin, Stefan Busse, Katharina Braun, Zbigniew Jankowski, Bernhard Bogerts, Tomasz GosAbstract:The central serotonergic system is implicated differentially in the pathogenesis of depression and Schizophrenia. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in both disorders. The study was carried out on paraffin-embedded brains from 27 depressed (15 major depressive disorder, MDD and 12 bipolar disorder, BD) and 17 Schizophrenia (9 Residual and 8 paranoid) patients and 28 matched controls without mental disorders. The transcriptional activity of ribosomal DNA (rDNA) in DRN neurons was evaluated by the AgNOR silver staining method. A significant effect of diagnosis on rDNA activity was found in the cumulative analysis of all DRN subnuclei. Further analysis revealed an increase in this activity in Residual (but not paranoid) Schizophrenia compared to depressed (both MDD and BD) patients. The effect was most probably neither confounded by suicide nor related to antidepressant and antipsychotic medication. Our findings suggest that increased activity of rDNA in DRN neurons is a distinct phenomenon in Residual Schizophrenia, related presumably to differentially disturbed inputs to the DRN and/or their local transformation compared with depressive episodes in patients with affective disorders.
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Ribosomal DNA transcription in the dorsal raphe nucleus is increased in Residual but not in paranoid Schizophrenia
European Archives of Psychiatry and Clinical Neuroscience, 2015Co-Authors: Marta Krzyżanowska, Johann Steiner, Hans-gert Bernstein, Ralf Brisch, Christian Mawrin, Stefan Busse, Katharina Braun, Zbigniew Jankowski, Bernhard Bogerts, Tomasz GosAbstract:The central serotonergic system is implicated in the pathogenesis of Schizophrenia, where the imbalance between dopamine, serotonin and glutamate plays a key pathophysiological role. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in Schizophrenia patients. The study was carried out on paraffin-embedded brains from 17 (8 paranoid and 9 Residual) Schizophrenia patients and 28 matched controls without mental disorders. The transcriptional activity of ribosomal DNA (rDNA) in DRN neurons was evaluated by the AgNOR silver-staining method. An increased rDNA transcriptional activity was found in Schizophrenia patients in the cumulative analysis of all DRN subnuclei ( t test, P = 0.02). Further subgroup analysis revealed that it was an effect specific for Residual Schizophrenia versus paranoid Schizophrenia or control groups (ANOVA, P = 0.002). This effect was confounded neither by suicide nor by antipsychotic medication. Our findings suggest that increased activity of rDNA in DRN neurons is a distinct phenomenon in Schizophrenia, particularly in Residual patients. An activation of the rDNA transcription in DRN neurons may represent a compensatory mechanism to overcome the previously described prefrontal serotonergic hypofunction in this diagnostic subgroup.
Christian Mawrin - One of the best experts on this subject based on the ideXlab platform.
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gabaergic system impairment in the hippocampus and superior temporal gyrus of patients with paranoid Schizophrenia a post mortem study
Schizophrenia Research, 2016Co-Authors: Johann Steiner, Hans-gert Bernstein, Henrik Dobrowolny, Ralf Brisch, Christian Mawrin, Katharina Braun, Zbigniew Jankowski, Kolja Schiltz, Marta Krzyzanowska, Andrea SchmittAbstract:Background: Glutamic acid decarboxylase (GAD) is a key enzyme in GABA synthesis and alterations in GABAergic neurotransmission related to glial abnormalities are thought to play a crucial role in the pathophysiology of Schizophrenia. This study aimed to identify potential differences regarding the neuropil expression of GAD between paranoid and Residual Schizophrenia. Methods: GAD65/67 immunostained histological sections were evaluated by quantitative densitometric analysis of GAD-immunoreactive (ir) neuropil. Regions of interest were the hippocampal formation (CA1 field and dentate gyrus [DG]), superior temporal gyrus (STG), and laterodorsal thalamic nucleus (LD). Data from 16 post-mortem Schizophrenia patient samples (10 paranoid and 6 Residual Schizophrenia cases) were compared with those from 16 matched controls. Results: Overall, Schizophrenia patients showed a lower GAD-ir neuropil density (P=0.014), particularly in the right CA1 (P = 0.033). However, the diagnostic subgroups differed significantly (P < 0.001), mainly because of lower right CA1 GAD-ir neuropil density in paranoid versus Residual patients (P = 0.036) and controls (P < 0.003). Significant GAD-ir neuropil reduction was also detected in the right STG layer V of paranoid versus Residual Schizophrenia cases (P = 0.042). GAD-ir neuropil density correlated positively with antipsychotic dosage, particularly in CA1 (right: r = 0.850, P = 0.004;left: r = 0.800, P = 0.010). Conclusion: Our finding of decreased relative density of GAD-ir neuropil suggests hypofunction of the GABAergic system, particularly in hippocampal CA1 field and STG layer V of patients with paranoid Schizophrenia. The finding that antipsychotic medication seems to counterbalance GABAergic hypofunction in Schizophrenia patients suggests the possibility of exploring new treatment avenues which target this system. (C) 2016 Elsevier B.V. All rights reserved.
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Increased density of DISC1-immunoreactive oligodendroglial cells in fronto-parietal white matter of patients with paranoid Schizophrenia
European Archives of Psychiatry and Clinical Neuroscience, 2016Co-Authors: Hans-gert Bernstein, Johann Steiner, Henrik Dobrowolny, Christian Mawrin, Esther Jauch, Bernhard BogertsAbstract:Profound white matter abnormalities have repeatedly been described in Schizophrenia, which involve the altered expression of numerous oligodendrocyte-associated genes. Transcripts of the disrupted-in-Schizophrenia 1 ( DISC1 ) gene, a key susceptibility factor in Schizophrenia, have recently been shown to be expressed by oligodendroglial cells and to negatively regulate oligodendrocyte differentiation and maturation. To learn more about the putative role(s) of oligodendroglia-associated DISC1 in Schizophrenia, we analyzed the density of DISC1-immunoreactive oligodendrocytes in the fronto-parietal white matter in postmortem brains of patients with Schizophrenia. Compared with controls ( N = 12) and cases with undifferentiated/Residual Schizophrenia ( N = 6), there was a significantly increased density of DISC1-expressing glial cells in paranoid Schizophrenia ( N = 12), which unlikely resulted from neuroleptic treatment. Pathophysiologically, over-expression of DISC1 protein(s) in white matter oligodendrocytes might add to the reduced levels of two myelin markers, 2′,3′-cyclic-nucleotide 3′-phosphodiesterase and myelin basic protein in Schizophrenia. Moreover, it might significantly contribute to cell cycle abnormalities as well as to deficits in oligodendroglial cell differentiation and maturation found in Schizophrenia.
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GABAergic system impairment in the hippocampus and superior temporal gyrus of patients with paranoid Schizophrenia: A post-mortem study.
Schizophrenia research, 2016Co-Authors: Johann Steiner, Hans-gert Bernstein, Henrik Dobrowolny, Ralf Brisch, Christian Mawrin, Marta Krzyżanowska, Katharina Braun, Zbigniew Jankowski, Kolja Schiltz, Andrea SchmittAbstract:Glutamic acid decarboxylase (GAD) is a key enzyme in GABA synthesis and alterations in GABAergic neurotransmission related to glial abnormalities are thought to play a crucial role in the pathophysiology of Schizophrenia. This study aimed to identify potential differences regarding the neuropil expression of GAD between paranoid and Residual Schizophrenia. GAD65/67 immunostained histological sections were evaluated by quantitative densitometric analysis of GAD-immunoreactive (ir) neuropil. Regions of interest were the hippocampal formation (CA1 field and dentate gyrus [DG]), superior temporal gyrus (STG), and laterodorsal thalamic nucleus (LD). Data from 16 post-mortem Schizophrenia patient samples (10 paranoid and 6 Residual Schizophrenia cases) were compared with those from 16 matched controls. Overall, Schizophrenia patients showed a lower GAD-ir neuropil density (P=0.014), particularly in the right CA1 (P=0.033). However, the diagnostic subgroups differed significantly (P<0.001), mainly because of lower right CA1 GAD-ir neuropil density in paranoid versus Residual patients (P=0.036) and controls (P<0.003). Significant GAD-ir neuropil reduction was also detected in the right STG layer V of paranoid versus Residual Schizophrenia cases (P=0.042). GAD-ir neuropil density correlated positively with antipsychotic dosage, particularly in CA1 (right: r=0.850, P=0.004; left: r=0.800, P=0.010). Our finding of decreased relative density of GAD-ir neuropil suggests hypofunction of the GABAergic system, particularly in hippocampal CA1 field and STG layer V of patients with paranoid Schizophrenia. The finding that antipsychotic medication seems to counterbalance GABAergic hypofunction in Schizophrenia patients suggests the possibility of exploring new treatment avenues which target this system. Copyright © 2016 Elsevier B.V. All rights reserved.
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Ribosomal DNA transcription in dorsal raphe nucleus neurons is increased in Residual Schizophrenia compared to depressed patients with affective disorders
Psychiatry research, 2015Co-Authors: Marta Krzyżanowska, Johann Steiner, Hans-gert Bernstein, Ralf Brisch, Christian Mawrin, Stefan Busse, Katharina Braun, Zbigniew Jankowski, Bernhard Bogerts, Tomasz GosAbstract:The central serotonergic system is implicated differentially in the pathogenesis of depression and Schizophrenia. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in both disorders. The study was carried out on paraffin-embedded brains from 27 depressed (15 major depressive disorder, MDD and 12 bipolar disorder, BD) and 17 Schizophrenia (9 Residual and 8 paranoid) patients and 28 matched controls without mental disorders. The transcriptional activity of ribosomal DNA (rDNA) in DRN neurons was evaluated by the AgNOR silver staining method. A significant effect of diagnosis on rDNA activity was found in the cumulative analysis of all DRN subnuclei. Further analysis revealed an increase in this activity in Residual (but not paranoid) Schizophrenia compared to depressed (both MDD and BD) patients. The effect was most probably neither confounded by suicide nor related to antidepressant and antipsychotic medication. Our findings suggest that increased activity of rDNA in DRN neurons is a distinct phenomenon in Residual Schizophrenia, related presumably to differentially disturbed inputs to the DRN and/or their local transformation compared with depressive episodes in patients with affective disorders.
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Ribosomal DNA transcription in the dorsal raphe nucleus is increased in Residual but not in paranoid Schizophrenia
European Archives of Psychiatry and Clinical Neuroscience, 2015Co-Authors: Marta Krzyżanowska, Johann Steiner, Hans-gert Bernstein, Ralf Brisch, Christian Mawrin, Stefan Busse, Katharina Braun, Zbigniew Jankowski, Bernhard Bogerts, Tomasz GosAbstract:The central serotonergic system is implicated in the pathogenesis of Schizophrenia, where the imbalance between dopamine, serotonin and glutamate plays a key pathophysiological role. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in Schizophrenia patients. The study was carried out on paraffin-embedded brains from 17 (8 paranoid and 9 Residual) Schizophrenia patients and 28 matched controls without mental disorders. The transcriptional activity of ribosomal DNA (rDNA) in DRN neurons was evaluated by the AgNOR silver-staining method. An increased rDNA transcriptional activity was found in Schizophrenia patients in the cumulative analysis of all DRN subnuclei ( t test, P = 0.02). Further subgroup analysis revealed that it was an effect specific for Residual Schizophrenia versus paranoid Schizophrenia or control groups (ANOVA, P = 0.002). This effect was confounded neither by suicide nor by antipsychotic medication. Our findings suggest that increased activity of rDNA in DRN neurons is a distinct phenomenon in Schizophrenia, particularly in Residual patients. An activation of the rDNA transcription in DRN neurons may represent a compensatory mechanism to overcome the previously described prefrontal serotonergic hypofunction in this diagnostic subgroup.
Ralf Brisch - One of the best experts on this subject based on the ideXlab platform.
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gabaergic system impairment in the hippocampus and superior temporal gyrus of patients with paranoid Schizophrenia a post mortem study
Schizophrenia Research, 2016Co-Authors: Johann Steiner, Hans-gert Bernstein, Henrik Dobrowolny, Ralf Brisch, Christian Mawrin, Katharina Braun, Zbigniew Jankowski, Kolja Schiltz, Marta Krzyzanowska, Andrea SchmittAbstract:Background: Glutamic acid decarboxylase (GAD) is a key enzyme in GABA synthesis and alterations in GABAergic neurotransmission related to glial abnormalities are thought to play a crucial role in the pathophysiology of Schizophrenia. This study aimed to identify potential differences regarding the neuropil expression of GAD between paranoid and Residual Schizophrenia. Methods: GAD65/67 immunostained histological sections were evaluated by quantitative densitometric analysis of GAD-immunoreactive (ir) neuropil. Regions of interest were the hippocampal formation (CA1 field and dentate gyrus [DG]), superior temporal gyrus (STG), and laterodorsal thalamic nucleus (LD). Data from 16 post-mortem Schizophrenia patient samples (10 paranoid and 6 Residual Schizophrenia cases) were compared with those from 16 matched controls. Results: Overall, Schizophrenia patients showed a lower GAD-ir neuropil density (P=0.014), particularly in the right CA1 (P = 0.033). However, the diagnostic subgroups differed significantly (P < 0.001), mainly because of lower right CA1 GAD-ir neuropil density in paranoid versus Residual patients (P = 0.036) and controls (P < 0.003). Significant GAD-ir neuropil reduction was also detected in the right STG layer V of paranoid versus Residual Schizophrenia cases (P = 0.042). GAD-ir neuropil density correlated positively with antipsychotic dosage, particularly in CA1 (right: r = 0.850, P = 0.004;left: r = 0.800, P = 0.010). Conclusion: Our finding of decreased relative density of GAD-ir neuropil suggests hypofunction of the GABAergic system, particularly in hippocampal CA1 field and STG layer V of patients with paranoid Schizophrenia. The finding that antipsychotic medication seems to counterbalance GABAergic hypofunction in Schizophrenia patients suggests the possibility of exploring new treatment avenues which target this system. (C) 2016 Elsevier B.V. All rights reserved.
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GABAergic system impairment in the hippocampus and superior temporal gyrus of patients with paranoid Schizophrenia: A post-mortem study.
Schizophrenia research, 2016Co-Authors: Johann Steiner, Hans-gert Bernstein, Henrik Dobrowolny, Ralf Brisch, Christian Mawrin, Marta Krzyżanowska, Katharina Braun, Zbigniew Jankowski, Kolja Schiltz, Andrea SchmittAbstract:Glutamic acid decarboxylase (GAD) is a key enzyme in GABA synthesis and alterations in GABAergic neurotransmission related to glial abnormalities are thought to play a crucial role in the pathophysiology of Schizophrenia. This study aimed to identify potential differences regarding the neuropil expression of GAD between paranoid and Residual Schizophrenia. GAD65/67 immunostained histological sections were evaluated by quantitative densitometric analysis of GAD-immunoreactive (ir) neuropil. Regions of interest were the hippocampal formation (CA1 field and dentate gyrus [DG]), superior temporal gyrus (STG), and laterodorsal thalamic nucleus (LD). Data from 16 post-mortem Schizophrenia patient samples (10 paranoid and 6 Residual Schizophrenia cases) were compared with those from 16 matched controls. Overall, Schizophrenia patients showed a lower GAD-ir neuropil density (P=0.014), particularly in the right CA1 (P=0.033). However, the diagnostic subgroups differed significantly (P<0.001), mainly because of lower right CA1 GAD-ir neuropil density in paranoid versus Residual patients (P=0.036) and controls (P<0.003). Significant GAD-ir neuropil reduction was also detected in the right STG layer V of paranoid versus Residual Schizophrenia cases (P=0.042). GAD-ir neuropil density correlated positively with antipsychotic dosage, particularly in CA1 (right: r=0.850, P=0.004; left: r=0.800, P=0.010). Our finding of decreased relative density of GAD-ir neuropil suggests hypofunction of the GABAergic system, particularly in hippocampal CA1 field and STG layer V of patients with paranoid Schizophrenia. The finding that antipsychotic medication seems to counterbalance GABAergic hypofunction in Schizophrenia patients suggests the possibility of exploring new treatment avenues which target this system. Copyright © 2016 Elsevier B.V. All rights reserved.
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Ribosomal DNA transcription in dorsal raphe nucleus neurons is increased in Residual Schizophrenia compared to depressed patients with affective disorders
Psychiatry research, 2015Co-Authors: Marta Krzyżanowska, Johann Steiner, Hans-gert Bernstein, Ralf Brisch, Christian Mawrin, Stefan Busse, Katharina Braun, Zbigniew Jankowski, Bernhard Bogerts, Tomasz GosAbstract:The central serotonergic system is implicated differentially in the pathogenesis of depression and Schizophrenia. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in both disorders. The study was carried out on paraffin-embedded brains from 27 depressed (15 major depressive disorder, MDD and 12 bipolar disorder, BD) and 17 Schizophrenia (9 Residual and 8 paranoid) patients and 28 matched controls without mental disorders. The transcriptional activity of ribosomal DNA (rDNA) in DRN neurons was evaluated by the AgNOR silver staining method. A significant effect of diagnosis on rDNA activity was found in the cumulative analysis of all DRN subnuclei. Further analysis revealed an increase in this activity in Residual (but not paranoid) Schizophrenia compared to depressed (both MDD and BD) patients. The effect was most probably neither confounded by suicide nor related to antidepressant and antipsychotic medication. Our findings suggest that increased activity of rDNA in DRN neurons is a distinct phenomenon in Residual Schizophrenia, related presumably to differentially disturbed inputs to the DRN and/or their local transformation compared with depressive episodes in patients with affective disorders.
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Ribosomal DNA transcription in the dorsal raphe nucleus is increased in Residual but not in paranoid Schizophrenia
European Archives of Psychiatry and Clinical Neuroscience, 2015Co-Authors: Marta Krzyżanowska, Johann Steiner, Hans-gert Bernstein, Ralf Brisch, Christian Mawrin, Stefan Busse, Katharina Braun, Zbigniew Jankowski, Bernhard Bogerts, Tomasz GosAbstract:The central serotonergic system is implicated in the pathogenesis of Schizophrenia, where the imbalance between dopamine, serotonin and glutamate plays a key pathophysiological role. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in Schizophrenia patients. The study was carried out on paraffin-embedded brains from 17 (8 paranoid and 9 Residual) Schizophrenia patients and 28 matched controls without mental disorders. The transcriptional activity of ribosomal DNA (rDNA) in DRN neurons was evaluated by the AgNOR silver-staining method. An increased rDNA transcriptional activity was found in Schizophrenia patients in the cumulative analysis of all DRN subnuclei ( t test, P = 0.02). Further subgroup analysis revealed that it was an effect specific for Residual Schizophrenia versus paranoid Schizophrenia or control groups (ANOVA, P = 0.002). This effect was confounded neither by suicide nor by antipsychotic medication. Our findings suggest that increased activity of rDNA in DRN neurons is a distinct phenomenon in Schizophrenia, particularly in Residual patients. An activation of the rDNA transcription in DRN neurons may represent a compensatory mechanism to overcome the previously described prefrontal serotonergic hypofunction in this diagnostic subgroup.
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Different distribution patterns of lymphocytes and microglia in the hippocampus of patients with Residual versus paranoid Schizophrenia: further evidence for disease course-related immune alterations?
Brain behavior and immunity, 2012Co-Authors: Stefan Busse, Hendrik Bielau, Ralf Brisch, Tomasz Gos, Christian Mawrin, Kolja Schiltz, Andrea Schmitt, Mandy Busse, Wolfgang Jordan, Ulf J. MüllerAbstract:Certain cytokines have been identified in the peripheral blood as trait markers of Schizophrenia, while others are considered relapse-related state markers. Furthermore, data from peripheral blood, cerebrospinal fluid (CSF) and nuclear imaging studies suggest that (1) blood-brain barrier (BBB) dysfunction (e.g., immigration of lymphocytes into brain tissue and intrathecal antibody production) correlates with the development of negative symptoms, while (2) the brain's mononuclear phagocyte system (microglial cells) is activated during acute psychosis. Based on these neuroinflammatory hypotheses, we have quantified the numerical density of immunostained CD3+ T-lymphocytes, CD20+ B-lymphocytes, and HLA-DR+ microglial cells in the posterior hippocampus of 17 Schizophrenia patients and 11 matched controls. Disease course-related immune alterations were considered by a separate analysis of Residual (prevailing negative symptoms, n=7) and paranoid (prominent positive symptoms, n=10) Schizophrenia cases. Higher densities of CD3+ and CD20+ lymphocytes were observed in Residual versus paranoid Schizophrenia (CD 3: left: P=0.047, right: P=0.038; CD20: left: P=0.020, right: P=0.010) and controls (CD3: left: P=0.057, right: P=0.069; CD20: left: P=0.008, right: P=0.006). In contrast, HLA-DR+ microglia were increased in paranoid Schizophrenia versus Residual Schizophrenia (left: P=0.030, right: P=0.012). A similar trend emerged when this group was compared to controls (left: P=0.090, right: P=0.090). BBB impairment and infiltration of T cells and B cells may contribute to the pathophysiology of Residual Schizophrenia, while microglial activation seems to play a role in paranoid Schizophrenia. The identification of diverse immune endophenotypes may facilitate the development of distinct anti-inflammatory Schizophrenia therapies to normalize BBB function, (auto)antibody production or microglial activity.
Andrea Schmitt - One of the best experts on this subject based on the ideXlab platform.
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gabaergic system impairment in the hippocampus and superior temporal gyrus of patients with paranoid Schizophrenia a post mortem study
Schizophrenia Research, 2016Co-Authors: Johann Steiner, Hans-gert Bernstein, Henrik Dobrowolny, Ralf Brisch, Christian Mawrin, Katharina Braun, Zbigniew Jankowski, Kolja Schiltz, Marta Krzyzanowska, Andrea SchmittAbstract:Background: Glutamic acid decarboxylase (GAD) is a key enzyme in GABA synthesis and alterations in GABAergic neurotransmission related to glial abnormalities are thought to play a crucial role in the pathophysiology of Schizophrenia. This study aimed to identify potential differences regarding the neuropil expression of GAD between paranoid and Residual Schizophrenia. Methods: GAD65/67 immunostained histological sections were evaluated by quantitative densitometric analysis of GAD-immunoreactive (ir) neuropil. Regions of interest were the hippocampal formation (CA1 field and dentate gyrus [DG]), superior temporal gyrus (STG), and laterodorsal thalamic nucleus (LD). Data from 16 post-mortem Schizophrenia patient samples (10 paranoid and 6 Residual Schizophrenia cases) were compared with those from 16 matched controls. Results: Overall, Schizophrenia patients showed a lower GAD-ir neuropil density (P=0.014), particularly in the right CA1 (P = 0.033). However, the diagnostic subgroups differed significantly (P < 0.001), mainly because of lower right CA1 GAD-ir neuropil density in paranoid versus Residual patients (P = 0.036) and controls (P < 0.003). Significant GAD-ir neuropil reduction was also detected in the right STG layer V of paranoid versus Residual Schizophrenia cases (P = 0.042). GAD-ir neuropil density correlated positively with antipsychotic dosage, particularly in CA1 (right: r = 0.850, P = 0.004;left: r = 0.800, P = 0.010). Conclusion: Our finding of decreased relative density of GAD-ir neuropil suggests hypofunction of the GABAergic system, particularly in hippocampal CA1 field and STG layer V of patients with paranoid Schizophrenia. The finding that antipsychotic medication seems to counterbalance GABAergic hypofunction in Schizophrenia patients suggests the possibility of exploring new treatment avenues which target this system. (C) 2016 Elsevier B.V. All rights reserved.
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GABAergic system impairment in the hippocampus and superior temporal gyrus of patients with paranoid Schizophrenia: A post-mortem study.
Schizophrenia research, 2016Co-Authors: Johann Steiner, Hans-gert Bernstein, Henrik Dobrowolny, Ralf Brisch, Christian Mawrin, Marta Krzyżanowska, Katharina Braun, Zbigniew Jankowski, Kolja Schiltz, Andrea SchmittAbstract:Glutamic acid decarboxylase (GAD) is a key enzyme in GABA synthesis and alterations in GABAergic neurotransmission related to glial abnormalities are thought to play a crucial role in the pathophysiology of Schizophrenia. This study aimed to identify potential differences regarding the neuropil expression of GAD between paranoid and Residual Schizophrenia. GAD65/67 immunostained histological sections were evaluated by quantitative densitometric analysis of GAD-immunoreactive (ir) neuropil. Regions of interest were the hippocampal formation (CA1 field and dentate gyrus [DG]), superior temporal gyrus (STG), and laterodorsal thalamic nucleus (LD). Data from 16 post-mortem Schizophrenia patient samples (10 paranoid and 6 Residual Schizophrenia cases) were compared with those from 16 matched controls. Overall, Schizophrenia patients showed a lower GAD-ir neuropil density (P=0.014), particularly in the right CA1 (P=0.033). However, the diagnostic subgroups differed significantly (P<0.001), mainly because of lower right CA1 GAD-ir neuropil density in paranoid versus Residual patients (P=0.036) and controls (P<0.003). Significant GAD-ir neuropil reduction was also detected in the right STG layer V of paranoid versus Residual Schizophrenia cases (P=0.042). GAD-ir neuropil density correlated positively with antipsychotic dosage, particularly in CA1 (right: r=0.850, P=0.004; left: r=0.800, P=0.010). Our finding of decreased relative density of GAD-ir neuropil suggests hypofunction of the GABAergic system, particularly in hippocampal CA1 field and STG layer V of patients with paranoid Schizophrenia. The finding that antipsychotic medication seems to counterbalance GABAergic hypofunction in Schizophrenia patients suggests the possibility of exploring new treatment avenues which target this system. Copyright © 2016 Elsevier B.V. All rights reserved.
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Different distribution patterns of lymphocytes and microglia in the hippocampus of patients with Residual versus paranoid Schizophrenia: further evidence for disease course-related immune alterations?
Brain behavior and immunity, 2012Co-Authors: Stefan Busse, Hendrik Bielau, Ralf Brisch, Tomasz Gos, Christian Mawrin, Kolja Schiltz, Andrea Schmitt, Mandy Busse, Wolfgang Jordan, Ulf J. MüllerAbstract:Certain cytokines have been identified in the peripheral blood as trait markers of Schizophrenia, while others are considered relapse-related state markers. Furthermore, data from peripheral blood, cerebrospinal fluid (CSF) and nuclear imaging studies suggest that (1) blood-brain barrier (BBB) dysfunction (e.g., immigration of lymphocytes into brain tissue and intrathecal antibody production) correlates with the development of negative symptoms, while (2) the brain's mononuclear phagocyte system (microglial cells) is activated during acute psychosis. Based on these neuroinflammatory hypotheses, we have quantified the numerical density of immunostained CD3+ T-lymphocytes, CD20+ B-lymphocytes, and HLA-DR+ microglial cells in the posterior hippocampus of 17 Schizophrenia patients and 11 matched controls. Disease course-related immune alterations were considered by a separate analysis of Residual (prevailing negative symptoms, n=7) and paranoid (prominent positive symptoms, n=10) Schizophrenia cases. Higher densities of CD3+ and CD20+ lymphocytes were observed in Residual versus paranoid Schizophrenia (CD 3: left: P=0.047, right: P=0.038; CD20: left: P=0.020, right: P=0.010) and controls (CD3: left: P=0.057, right: P=0.069; CD20: left: P=0.008, right: P=0.006). In contrast, HLA-DR+ microglia were increased in paranoid Schizophrenia versus Residual Schizophrenia (left: P=0.030, right: P=0.012). A similar trend emerged when this group was compared to controls (left: P=0.090, right: P=0.090). BBB impairment and infiltration of T cells and B cells may contribute to the pathophysiology of Residual Schizophrenia, while microglial activation seems to play a role in paranoid Schizophrenia. The identification of diverse immune endophenotypes may facilitate the development of distinct anti-inflammatory Schizophrenia therapies to normalize BBB function, (auto)antibody production or microglial activity.
Hans-gert Bernstein - One of the best experts on this subject based on the ideXlab platform.
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gabaergic system impairment in the hippocampus and superior temporal gyrus of patients with paranoid Schizophrenia a post mortem study
Schizophrenia Research, 2016Co-Authors: Johann Steiner, Hans-gert Bernstein, Henrik Dobrowolny, Ralf Brisch, Christian Mawrin, Katharina Braun, Zbigniew Jankowski, Kolja Schiltz, Marta Krzyzanowska, Andrea SchmittAbstract:Background: Glutamic acid decarboxylase (GAD) is a key enzyme in GABA synthesis and alterations in GABAergic neurotransmission related to glial abnormalities are thought to play a crucial role in the pathophysiology of Schizophrenia. This study aimed to identify potential differences regarding the neuropil expression of GAD between paranoid and Residual Schizophrenia. Methods: GAD65/67 immunostained histological sections were evaluated by quantitative densitometric analysis of GAD-immunoreactive (ir) neuropil. Regions of interest were the hippocampal formation (CA1 field and dentate gyrus [DG]), superior temporal gyrus (STG), and laterodorsal thalamic nucleus (LD). Data from 16 post-mortem Schizophrenia patient samples (10 paranoid and 6 Residual Schizophrenia cases) were compared with those from 16 matched controls. Results: Overall, Schizophrenia patients showed a lower GAD-ir neuropil density (P=0.014), particularly in the right CA1 (P = 0.033). However, the diagnostic subgroups differed significantly (P < 0.001), mainly because of lower right CA1 GAD-ir neuropil density in paranoid versus Residual patients (P = 0.036) and controls (P < 0.003). Significant GAD-ir neuropil reduction was also detected in the right STG layer V of paranoid versus Residual Schizophrenia cases (P = 0.042). GAD-ir neuropil density correlated positively with antipsychotic dosage, particularly in CA1 (right: r = 0.850, P = 0.004;left: r = 0.800, P = 0.010). Conclusion: Our finding of decreased relative density of GAD-ir neuropil suggests hypofunction of the GABAergic system, particularly in hippocampal CA1 field and STG layer V of patients with paranoid Schizophrenia. The finding that antipsychotic medication seems to counterbalance GABAergic hypofunction in Schizophrenia patients suggests the possibility of exploring new treatment avenues which target this system. (C) 2016 Elsevier B.V. All rights reserved.
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Increased density of DISC1-immunoreactive oligodendroglial cells in fronto-parietal white matter of patients with paranoid Schizophrenia
European Archives of Psychiatry and Clinical Neuroscience, 2016Co-Authors: Hans-gert Bernstein, Johann Steiner, Henrik Dobrowolny, Christian Mawrin, Esther Jauch, Bernhard BogertsAbstract:Profound white matter abnormalities have repeatedly been described in Schizophrenia, which involve the altered expression of numerous oligodendrocyte-associated genes. Transcripts of the disrupted-in-Schizophrenia 1 ( DISC1 ) gene, a key susceptibility factor in Schizophrenia, have recently been shown to be expressed by oligodendroglial cells and to negatively regulate oligodendrocyte differentiation and maturation. To learn more about the putative role(s) of oligodendroglia-associated DISC1 in Schizophrenia, we analyzed the density of DISC1-immunoreactive oligodendrocytes in the fronto-parietal white matter in postmortem brains of patients with Schizophrenia. Compared with controls ( N = 12) and cases with undifferentiated/Residual Schizophrenia ( N = 6), there was a significantly increased density of DISC1-expressing glial cells in paranoid Schizophrenia ( N = 12), which unlikely resulted from neuroleptic treatment. Pathophysiologically, over-expression of DISC1 protein(s) in white matter oligodendrocytes might add to the reduced levels of two myelin markers, 2′,3′-cyclic-nucleotide 3′-phosphodiesterase and myelin basic protein in Schizophrenia. Moreover, it might significantly contribute to cell cycle abnormalities as well as to deficits in oligodendroglial cell differentiation and maturation found in Schizophrenia.
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GABAergic system impairment in the hippocampus and superior temporal gyrus of patients with paranoid Schizophrenia: A post-mortem study.
Schizophrenia research, 2016Co-Authors: Johann Steiner, Hans-gert Bernstein, Henrik Dobrowolny, Ralf Brisch, Christian Mawrin, Marta Krzyżanowska, Katharina Braun, Zbigniew Jankowski, Kolja Schiltz, Andrea SchmittAbstract:Glutamic acid decarboxylase (GAD) is a key enzyme in GABA synthesis and alterations in GABAergic neurotransmission related to glial abnormalities are thought to play a crucial role in the pathophysiology of Schizophrenia. This study aimed to identify potential differences regarding the neuropil expression of GAD between paranoid and Residual Schizophrenia. GAD65/67 immunostained histological sections were evaluated by quantitative densitometric analysis of GAD-immunoreactive (ir) neuropil. Regions of interest were the hippocampal formation (CA1 field and dentate gyrus [DG]), superior temporal gyrus (STG), and laterodorsal thalamic nucleus (LD). Data from 16 post-mortem Schizophrenia patient samples (10 paranoid and 6 Residual Schizophrenia cases) were compared with those from 16 matched controls. Overall, Schizophrenia patients showed a lower GAD-ir neuropil density (P=0.014), particularly in the right CA1 (P=0.033). However, the diagnostic subgroups differed significantly (P<0.001), mainly because of lower right CA1 GAD-ir neuropil density in paranoid versus Residual patients (P=0.036) and controls (P<0.003). Significant GAD-ir neuropil reduction was also detected in the right STG layer V of paranoid versus Residual Schizophrenia cases (P=0.042). GAD-ir neuropil density correlated positively with antipsychotic dosage, particularly in CA1 (right: r=0.850, P=0.004; left: r=0.800, P=0.010). Our finding of decreased relative density of GAD-ir neuropil suggests hypofunction of the GABAergic system, particularly in hippocampal CA1 field and STG layer V of patients with paranoid Schizophrenia. The finding that antipsychotic medication seems to counterbalance GABAergic hypofunction in Schizophrenia patients suggests the possibility of exploring new treatment avenues which target this system. Copyright © 2016 Elsevier B.V. All rights reserved.
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Ribosomal DNA transcription in dorsal raphe nucleus neurons is increased in Residual Schizophrenia compared to depressed patients with affective disorders
Psychiatry research, 2015Co-Authors: Marta Krzyżanowska, Johann Steiner, Hans-gert Bernstein, Ralf Brisch, Christian Mawrin, Stefan Busse, Katharina Braun, Zbigniew Jankowski, Bernhard Bogerts, Tomasz GosAbstract:The central serotonergic system is implicated differentially in the pathogenesis of depression and Schizophrenia. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in both disorders. The study was carried out on paraffin-embedded brains from 27 depressed (15 major depressive disorder, MDD and 12 bipolar disorder, BD) and 17 Schizophrenia (9 Residual and 8 paranoid) patients and 28 matched controls without mental disorders. The transcriptional activity of ribosomal DNA (rDNA) in DRN neurons was evaluated by the AgNOR silver staining method. A significant effect of diagnosis on rDNA activity was found in the cumulative analysis of all DRN subnuclei. Further analysis revealed an increase in this activity in Residual (but not paranoid) Schizophrenia compared to depressed (both MDD and BD) patients. The effect was most probably neither confounded by suicide nor related to antidepressant and antipsychotic medication. Our findings suggest that increased activity of rDNA in DRN neurons is a distinct phenomenon in Residual Schizophrenia, related presumably to differentially disturbed inputs to the DRN and/or their local transformation compared with depressive episodes in patients with affective disorders.
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Ribosomal DNA transcription in the dorsal raphe nucleus is increased in Residual but not in paranoid Schizophrenia
European Archives of Psychiatry and Clinical Neuroscience, 2015Co-Authors: Marta Krzyżanowska, Johann Steiner, Hans-gert Bernstein, Ralf Brisch, Christian Mawrin, Stefan Busse, Katharina Braun, Zbigniew Jankowski, Bernhard Bogerts, Tomasz GosAbstract:The central serotonergic system is implicated in the pathogenesis of Schizophrenia, where the imbalance between dopamine, serotonin and glutamate plays a key pathophysiological role. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in Schizophrenia patients. The study was carried out on paraffin-embedded brains from 17 (8 paranoid and 9 Residual) Schizophrenia patients and 28 matched controls without mental disorders. The transcriptional activity of ribosomal DNA (rDNA) in DRN neurons was evaluated by the AgNOR silver-staining method. An increased rDNA transcriptional activity was found in Schizophrenia patients in the cumulative analysis of all DRN subnuclei ( t test, P = 0.02). Further subgroup analysis revealed that it was an effect specific for Residual Schizophrenia versus paranoid Schizophrenia or control groups (ANOVA, P = 0.002). This effect was confounded neither by suicide nor by antipsychotic medication. Our findings suggest that increased activity of rDNA in DRN neurons is a distinct phenomenon in Schizophrenia, particularly in Residual patients. An activation of the rDNA transcription in DRN neurons may represent a compensatory mechanism to overcome the previously described prefrontal serotonergic hypofunction in this diagnostic subgroup.