The Experts below are selected from a list of 219 Experts worldwide ranked by ideXlab platform
Brian Dean - One of the best experts on this subject based on the ideXlab platform.
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The neurobiology of APOE in Schizophrenia and mood disorders.
Frontiers in Bioscience, 2011Co-Authors: Andrew Gibbons, Madhara Udawela, Won Je Jeon, Lucy Brooks, Brian DeanAbstract:: APOE is a major component of several lipoproteins. In addition to its role as a lipid transport protein APOE also serves a dual role as a glial derived, synaptic signalling molecule and thought to play an important role in synaptic plasticity and cognition. Polymorphisms within the APOE gene have been associated with the incidence of Alzheimer's disease. In light of the similarities in the cognitive deficits experienced in both Alzheimer's disease and Schizophrenia as well as the comorbidity of depression in Alzheimer's disease, aberrant APOE signalling has been implicated in the pathologies of Schizophrenia and mood disorders. The Schizophrenia candidate gene, reelin, also shares common receptors with APOE, further supporting a role for APOE in the Pathology of these disorders. This review will summarise the current understanding of the involvement of APOE and its receptors in the symptomatology and Pathology of Schizophrenia and mood disorders and the implications of this involvement for drug treatment.
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muscarinic receptors do they have a role in the Pathology and treatment of Schizophrenia
Journal of Neurochemistry, 2008Co-Authors: Elizabeth Scarr, Brian DeanAbstract:The high affinity of antipsychotic drugs for the dopamine D2 receptor focused attention onto the role of these receptors in the genesis of psychoses and the Pathology of Schizophrenia. However, psychotic symptoms are only one aspect of the complex symptom profile associated with Schizophrenia. Therefore, research continues into other neurochemical systems and their potential roles in key features associated with Schizophrenia. Modulating the cholinergic system in attempts to treat Schizophrenia predates specific neurochemical hypotheses of the disorder. Cholinergic modulation has progressed from the use of coma therapy, through the use of anti-cholinergic drugs to control side-effects of older (typical) antipsychotic medications, to the development of drugs designed to specifically activate selected muscarinic receptors. This review presents data implicating a decrease in muscarinic receptors, particularly the M1 receptor, in the Pathology of Schizophrenia and explores the potential physiological consequences of such a change, drawing on data available from muscarinic receptor knockout mice as well as clinical and pre-clinical pharmacology. The body of evidence presented suggests that deficits in muscarinic receptors are associated with some forms of Schizophrenia and that targeting these receptors could prove to be of therapeutic benefit to patients with the disorder.
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altered hippocampal muscarinic m4 but not m1 receptor expression from subjects with Schizophrenia
Biological Psychiatry, 2007Co-Authors: Elizabeth Scarr, Suresh Sundram, Dahlia Keriakous, Brian DeanAbstract:Background Having shown a decrease in [3H]pirenzepine binding in the hippocampus from subjects with Schizophrenia, we wished to determine whether such a change in radioligand binding was associated with changes in hippocampal mRNA for the muscarinic1 (M1) and muscarinic4 (M4) receptors in tissue from different cohorts of subjects. Method The [3H]pirenzepine binding using autoradiography and in situ hybridization with oligonucleotides specific for muscarinic M1 and M4 receptors were completed using hippocampal tissue obtained postmortem from 20 control subjects and 20 subjects with Schizophrenia. Results The [3H]pirenzepine binding was decreased in the dentate gyrus (p < .05), CA3 (p < .01), CA2 (p < .05), and CA1 (p < .01) regions of the hippocampus from subjects with Schizophrenia. Levels of M4 mRNA varied with the diagnosis of Schizophrenia (p = .01), but significant region-specific changes were not apparent. Changes in levels of mRNA for the muscarinic M1 receptor were not detected with diagnosis. Conclusions This study suggests that decreases in hippocampal [3H]pirenzepine binding in subjects with Schizophrenia are most likely associated with widespread changes in expression levels of the M4 receptor. These data further implicate the hippocampal formation in the Pathology of Schizophrenia.
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5-HT2A and muscarinic receptors in Schizophrenia: a postmortem study.
Neuroscience Letters, 2005Co-Authors: Izuru Matsumoto, Yuki Inoue, Takeshi Iwazaki, Geoff Pavey, Brian DeanAbstract:Abstract Although evidence suggests that 5-HT 2A and muscarinic M1/M4 receptors are implicated in the Pathology of Schizophrenia, the results are not conclusive. In the present study we tested the hypothesis that binding of 5-HT 2A and M1/M4 receptors is altered in the postmortem brain of Schizophrenia subjects. Quantitative autoradiography was employed to measure [ 3 H]ketanserin binding to 5-HT 2A receptors and [ 3 H]pirenzepine binding to both M1 and M4 receptors in Brodmann's area 9 (BA9), caudate/putamen, and the hippocampal formation from six schizophrenic and six control subjects. A significant reduction in the density of 5HT 2A receptors in BA 9 of schizophrenic subjects was observed ( p = 0.036). No significant difference was observed in the density of 5HT 2A receptors in the hippocampus or caudate/putamen between the two groups. No significant changes in the density of M1/M4 receptors was observed in these three regions between the two groups. These findings support a possible involvement of the serotonergic system in the Pathology of Schizophrenia.
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understanding the Pathology of Schizophrenia the impact of high throughput screening of the genome and proteome in postmortem cns
Current Psychiatry Reviews, 2005Co-Authors: Brian Dean, Dahlia Keriakous, Elizabeth A. Thomas, Elizabeth ScarrAbstract:High-throughput screening technologies such as microarrays and 2D electrophoresis are powerful analytical tools particularly suited to investigating the pathologies of complex diseases. Schizophrenia is now widely recognised as a complex disorder resulting from the interplay between genetic predisposition to the illness and the effects of yet to be identified environmental factors. Based the hypothesis that the outcome of the interaction between genetic predisposition and environmental factors act to produce changes in protein expression in the CNS to cause Schizophrenia, a number of studies have used postmortem CNS and highthroughput screening technologies to identify potential pathological processes that might be involved in the Pathology of the disorder. This review attempts to place the current findings on gene and protein expression data in postmortem CNS from subjects with Schizophrenia into a perspective that allows hypotheses on the cause of the disorder to be formulated.
Elizabeth Scarr - One of the best experts on this subject based on the ideXlab platform.
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muscarinic receptors do they have a role in the Pathology and treatment of Schizophrenia
Journal of Neurochemistry, 2008Co-Authors: Elizabeth Scarr, Brian DeanAbstract:The high affinity of antipsychotic drugs for the dopamine D2 receptor focused attention onto the role of these receptors in the genesis of psychoses and the Pathology of Schizophrenia. However, psychotic symptoms are only one aspect of the complex symptom profile associated with Schizophrenia. Therefore, research continues into other neurochemical systems and their potential roles in key features associated with Schizophrenia. Modulating the cholinergic system in attempts to treat Schizophrenia predates specific neurochemical hypotheses of the disorder. Cholinergic modulation has progressed from the use of coma therapy, through the use of anti-cholinergic drugs to control side-effects of older (typical) antipsychotic medications, to the development of drugs designed to specifically activate selected muscarinic receptors. This review presents data implicating a decrease in muscarinic receptors, particularly the M1 receptor, in the Pathology of Schizophrenia and explores the potential physiological consequences of such a change, drawing on data available from muscarinic receptor knockout mice as well as clinical and pre-clinical pharmacology. The body of evidence presented suggests that deficits in muscarinic receptors are associated with some forms of Schizophrenia and that targeting these receptors could prove to be of therapeutic benefit to patients with the disorder.
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altered hippocampal muscarinic m4 but not m1 receptor expression from subjects with Schizophrenia
Biological Psychiatry, 2007Co-Authors: Elizabeth Scarr, Suresh Sundram, Dahlia Keriakous, Brian DeanAbstract:Background Having shown a decrease in [3H]pirenzepine binding in the hippocampus from subjects with Schizophrenia, we wished to determine whether such a change in radioligand binding was associated with changes in hippocampal mRNA for the muscarinic1 (M1) and muscarinic4 (M4) receptors in tissue from different cohorts of subjects. Method The [3H]pirenzepine binding using autoradiography and in situ hybridization with oligonucleotides specific for muscarinic M1 and M4 receptors were completed using hippocampal tissue obtained postmortem from 20 control subjects and 20 subjects with Schizophrenia. Results The [3H]pirenzepine binding was decreased in the dentate gyrus (p < .05), CA3 (p < .01), CA2 (p < .05), and CA1 (p < .01) regions of the hippocampus from subjects with Schizophrenia. Levels of M4 mRNA varied with the diagnosis of Schizophrenia (p = .01), but significant region-specific changes were not apparent. Changes in levels of mRNA for the muscarinic M1 receptor were not detected with diagnosis. Conclusions This study suggests that decreases in hippocampal [3H]pirenzepine binding in subjects with Schizophrenia are most likely associated with widespread changes in expression levels of the M4 receptor. These data further implicate the hippocampal formation in the Pathology of Schizophrenia.
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understanding the Pathology of Schizophrenia the impact of high throughput screening of the genome and proteome in postmortem cns
Current Psychiatry Reviews, 2005Co-Authors: Brian Dean, Dahlia Keriakous, Elizabeth A. Thomas, Elizabeth ScarrAbstract:High-throughput screening technologies such as microarrays and 2D electrophoresis are powerful analytical tools particularly suited to investigating the pathologies of complex diseases. Schizophrenia is now widely recognised as a complex disorder resulting from the interplay between genetic predisposition to the illness and the effects of yet to be identified environmental factors. Based the hypothesis that the outcome of the interaction between genetic predisposition and environmental factors act to produce changes in protein expression in the CNS to cause Schizophrenia, a number of studies have used postmortem CNS and highthroughput screening technologies to identify potential pathological processes that might be involved in the Pathology of the disorder. This review attempts to place the current findings on gene and protein expression data in postmortem CNS from subjects with Schizophrenia into a perspective that allows hypotheses on the cause of the disorder to be formulated.
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Increased levels of apolipoprotein E in the frontal cortex of subjects with Schizophrenia
Biological Psychiatry, 2003Co-Authors: Brian Dean, Elizabeth Scarr, Simon M. Laws, Eugene Hone, Kevin Taddei, Elizabeth A. Thomas, Clive Harper, Catriona Mcclean, Colin L. Masters, Nicola T. LautenschlagerAbstract:Abstract Background It is unclear whether altered expression of a specific isoform of apolipoprotein E (apoE) is associated with the Pathology of Schizophrenia. Methods To address whether apoE may be involved in the Pathology of Schizophrenia, we measured the genotypic and allelic frequency of polymorphisms in its gene and transcriptional regulatory region in DNA from Brodmann’s area (BA) 9 obtained postmortem from schizophrenic and control subjects as well as its levels in the same tissue using Western blot analysis. Results The genotypic or allelic frequencies of any polymorphism studied did not vary between diagnostic cohorts. There was a significant increase in the levels of apoE protein in BA 9 from the schizophrenic subjects (Mean ± SEM: 270 ± 8.3 vs. 238 ± 7.1 ng apoE/mg protein, p = .008) and a decrease in tissue from an analogous cortical region from rats treated with haloperidol compared with vehicle-treated animals (50 ± 6.4 vs. 116 ± 9.2 ng apoE/mg protein; p = .0002). Conclusions These data support the hypothesis that increased levels of apoE may be associated with the Pathology of Schizophrenia and that antipsychotic drugs decrease apoE levels as part of their therapeutic actions.
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Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with Schizophrenia and cannabis use.
Neuroscience, 2001Co-Authors: Brian Dean, Elizabeth Scarr, Suresh Sundram, Robyn Bradbury, David L. CopolovAbstract:A number of studies suggested that cannabis use can cause or exacerbate psychoses and may increase the risk of developing Schizophrenia. These findings suggest that changes in the cannabinoid system of the brain may be involved in the Pathology of Schizophrenia. To determine whether changes in the cannabinoid system were present in the brains of subjects with Schizophrenia, we used in situ radioligand binding and autoradiography to measure the binding of ( 3 H)CP-55940 to the cannabinoid-1 receptor in the dorsolateral prefrontal cortex (Brodmann's area 9), caudate-putamen and areas of the temporal lobe from schizophrenic and control subjects, some of whom had ingested cannabis close to death. There was an increase in the density of ( 3 H)CP-55940 binding to cannabinoid-1 receptors in the dorsolateral prefrontal cortex from subjects with Schizophrenia (mean^ S.E.M.: 142^ 9.9 vs 119^ 6.6 fmol/mg estimated tissue equivalents; P , 0.05) that was independent of recent cannabis ingestion. There was an increase in the density of cannabinoid-1 receptors in the caudate-putamen from subjects who had recently ingested cannabis (151^ 9.0 vs 123^ 7.2 fmol/mg estimated tissue equivalents; P , 0.05) that was independent of diagnoses. These data indicate that there are changes in cannabinoid-1 receptors in the dorsolateral prefrontal cortex that may prove to be associated with the Pathology of Schizophrenia. By contrast, changes in the density of cannabinoid-1 receptors may occur in the caudate-putamen in response to cannabis ingestion. q 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.
S R Hirsch - One of the best experts on this subject based on the ideXlab platform.
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nitric oxide free radicals and polyamines may have a role in the membrane Pathology of Schizophrenia
Neuropsychobiology, 1998Co-Authors: C N Ramchand, A Gliddon, S R HirschAbstract:Studies on skin fibroblasts in culture derived from schizophrenic and control subjects showed that polyamines are increased, nitrate levels are reduced and thiobarbituric acid reacting substances did
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role of polyamines in the membrane Pathology of Schizophrenia a study using fibroblasts from schizophrenic patients and normal controls
Schizophrenia Research, 1994Co-Authors: C N Ramchand, Angela E Gliddon, S R HirschAbstract:The polyamines putrescine, spermine, and spermidine play a major role in the regulation of cell growth and differentiation, metabolic pathways, and on cell membrane functions in mammalian systems. It has recently been suggested that polyamines may be involved in the pathophysiology of Schizophrenia. Moreover, several reports suggest that Schizophrenia may be associated with a generalized cell membrane abnormality. In view of these findings, we measured polyamine levels in cultured skin fibroblasts from schizophrenic patients and normal control subjects. There was a significant increase in the levels of spermidine and in total polyamines in fibroblasts and spermine in the culture medium from schizophrenic patients. This preliminary report suggests that polyamines may play an important role in the membrane abnormalities that have been reported in schizophrenic patients.
Bernhard Bogerts - One of the best experts on this subject based on the ideXlab platform.
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The Role of Dopamine in Schizophrenia from a Neurobiological and Evolutionary Perspective: Old Fashioned, but Still in Vogue
Frontiers in Psychiatry, 2014Co-Authors: Ralf Brisch, Bernhard Bogerts, Arthur Saniotis, Rainer Wolf, Hendrik Bielau, Hans-gert Bernstein, Johann Steiner, Katharina Braun, Zbigniew Jankowski, Jaliya KumaratilakeAbstract:Dopamine is an inhibitory neurotransmitter involved in the Pathology of Schizophrenia. The revised dopamine hypothesis states that dopamine abnormalities in the mesolimbic and prefrontal brain regions exist in Schizophrenia. However, recent research has indicated that glutamate, GABA, acetylcholine, and serotonin alterations are also involved in the Pathology of Schizophrenia. This review provides an in-depth analysis of dopamine in animal models of Schizophrenia and also focuses on dopamine and cognition. Furthermore, this review provides not only an overview of dopamine receptors and the antipsychotic effects of treatments targeting them but also an outline of dopamine and its interaction with other neurochemical models of Schizophrenia. The roles of dopamine in the evolution of the human brain and human mental abilities, which are affected in Schizophrenia patients, are also discussed.
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Increased Density of Prohibitin-Immunoreactive Oligodendrocytes in the Dorsolateral Prefrontal White Matter of Subjects with Schizophrenia Suggests Extraneuronal Roles for the Protein in the Disease
NeuroMolecular Medicine, 2012Co-Authors: Hans-gert Bernstein, Karlheinz Smalla, Andrea Schmitt, Johann Steiner, Diana Dürrschmidt, Gerburg Keilhoff, Henrik Dobrowolny, Michael R. Kreutz, Bernhard BogertsAbstract:Prohibitin has previously been implicated in the synaptic Pathology of Schizophrenia. The recently discovered abundant expression of prohibitin in human prefrontal oligodendrocytes raises the issue, whether this protein might also be part of the well-known white matter abnormalities in Schizophrenia. Hence, post-mortem brains of ten patients with Schizophrenia and ten matched control cases were investigated. Using a direct, 3D-counting technique we morphometrically analyzed the number and density of prohibitin-immunoreactive oligodendroglial cells in the left and right dorsolateral, anterior cingulate, and orbitofrontal cortex white matter. Additionally, we studied the prohibitin expression in different neuronal and non-neuronal cell populations in rat cell cultures. We could confirm the strong expression of prohibitin in oligodendrocytes. Intracellularly, the protein was localized to mitochondria and some cell nuclei. In Schizophrenia, the numerical density of prohibitin-expressing oligodendrocytes was significantly increased in the right dorsolateral white matter area. Taking into consideration the dual intracellular localization of prohibitin in oligodendrocyte mitochondria and cell nuclei, one may suggest an involvement of the protein in mitochondrial dysfunction and/or cycle abnormalities in Schizophrenia.
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a comparison of the synaptic proteome in human chronic Schizophrenia and rat ketamine psychosis suggest that prohibitin is involved in the synaptic Pathology of Schizophrenia
Molecular Psychiatry, 2008Co-Authors: Karlheinz Smalla, Marina Mikhaylova, Jale Sahin, H G Bernstein, Bernhard Bogerts, Andrea Schmitt, R C Van Der Schors, August B Smit, Ka Wan Li, Eckart D GundelfingerAbstract:Many studies in recent years suggest that Schizophrenia is a synaptic disease that crucially involves a hypofunction of N-methyl-D-aspartate receptor-mediated signaling. However, at present it is unclear how these pathological processes are reflected in the protein content of the synapse. We have employed two-dimensional gel electrophoresis in conjunction with mass spectrometry to characterize and compare the synaptic proteomes of the human left dorsolateral prefrontal cortex in chronic Schizophrenia and of the cerebral cortex of rats treated subchronically with ketamine. We found consistent changes in the synaptic proteomes of human schizophrenics and in rats with induced ketamine psychosis compared to controls. However, commonly regulated proteins between both groups were very limited and only prohibitin was found upregulated in both chronic Schizophrenia and the rat ketamine model. Prohibitin, however, could be a new potential marker for the synaptic Pathology of Schizophrenia and might be causally involved in the disease process.
Karlheinz Smalla - One of the best experts on this subject based on the ideXlab platform.
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Increased Density of Prohibitin-Immunoreactive Oligodendrocytes in the Dorsolateral Prefrontal White Matter of Subjects with Schizophrenia Suggests Extraneuronal Roles for the Protein in the Disease
NeuroMolecular Medicine, 2012Co-Authors: Hans-gert Bernstein, Karlheinz Smalla, Andrea Schmitt, Johann Steiner, Diana Dürrschmidt, Gerburg Keilhoff, Henrik Dobrowolny, Michael R. Kreutz, Bernhard BogertsAbstract:Prohibitin has previously been implicated in the synaptic Pathology of Schizophrenia. The recently discovered abundant expression of prohibitin in human prefrontal oligodendrocytes raises the issue, whether this protein might also be part of the well-known white matter abnormalities in Schizophrenia. Hence, post-mortem brains of ten patients with Schizophrenia and ten matched control cases were investigated. Using a direct, 3D-counting technique we morphometrically analyzed the number and density of prohibitin-immunoreactive oligodendroglial cells in the left and right dorsolateral, anterior cingulate, and orbitofrontal cortex white matter. Additionally, we studied the prohibitin expression in different neuronal and non-neuronal cell populations in rat cell cultures. We could confirm the strong expression of prohibitin in oligodendrocytes. Intracellularly, the protein was localized to mitochondria and some cell nuclei. In Schizophrenia, the numerical density of prohibitin-expressing oligodendrocytes was significantly increased in the right dorsolateral white matter area. Taking into consideration the dual intracellular localization of prohibitin in oligodendrocyte mitochondria and cell nuclei, one may suggest an involvement of the protein in mitochondrial dysfunction and/or cycle abnormalities in Schizophrenia.
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a comparison of the synaptic proteome in human chronic Schizophrenia and rat ketamine psychosis suggest that prohibitin is involved in the synaptic Pathology of Schizophrenia
Molecular Psychiatry, 2008Co-Authors: Karlheinz Smalla, Marina Mikhaylova, Jale Sahin, H G Bernstein, Bernhard Bogerts, Andrea Schmitt, R C Van Der Schors, August B Smit, Ka Wan Li, Eckart D GundelfingerAbstract:Many studies in recent years suggest that Schizophrenia is a synaptic disease that crucially involves a hypofunction of N-methyl-D-aspartate receptor-mediated signaling. However, at present it is unclear how these pathological processes are reflected in the protein content of the synapse. We have employed two-dimensional gel electrophoresis in conjunction with mass spectrometry to characterize and compare the synaptic proteomes of the human left dorsolateral prefrontal cortex in chronic Schizophrenia and of the cerebral cortex of rats treated subchronically with ketamine. We found consistent changes in the synaptic proteomes of human schizophrenics and in rats with induced ketamine psychosis compared to controls. However, commonly regulated proteins between both groups were very limited and only prohibitin was found upregulated in both chronic Schizophrenia and the rat ketamine model. Prohibitin, however, could be a new potential marker for the synaptic Pathology of Schizophrenia and might be causally involved in the disease process.