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Plasma and platelets glutamate levels in major psychoses
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8. Neurochemistryh4olecular Biology PLASMA AND PLATELETS GLUTAMATE LEVELS IN MAJOR PSYCHOSES AC. Altamura, M.C. Mauri, A. Ferrara, G. D’Andrea* Department of Psychiatry, University of Milan, 20122 Milan, Italy; *Department of Neurology, General Hospital Vicenza, Italy Excitatory aminoacids (EAA) in CNS, play an important role in neuronal plasticity, cell degeneration, and are also involved in Recently, a cognitive processes and memory acquisition. “glutamatergic theory” of schizophrenia has been envisaged where a failure of cortical glutamatergic projections modulating DA mesolimbic pathways has been hypothesized. 32 out-patients, diagnosed according to the DSM III-R as suffering from Schizophrenia (11 pt), Mood Disorders (15 pt), Anxiety Disorders (6 pt) and a control group (19 pt), entered into the study. All patients were off any psychotropic medication for at least 3 weeks. Plasma and platelet EAA determinations were carried out by means of a Millipore Waters HPLC system connected to a Perkin Elmer fluorescence spectrometer. Schizophrenic patients showed a trend towards an increase in glutamate plasma levels but it was statistically significant only in depressed patients. Glutamate platelet levels did not show any significant difference between patients and controls. The AA discuss the possible significance of these data in relation to the pathogenetic role of glutamate in Schizophrenia and Mood Disorders.
COULD ABERRANT NEUROTROPHIC ACTIVITY CAUSE SCHIZOPHRENIA? T. Anthony*, Stephen Rayport, Charles A. Kaufmann Donna
Department of Psychiatry, Columbia University; New York State Psychiatric Institute, 722 W. 168 St., New York, NY 10032, USA Alterations in neurotrophic factor (NTF) expression appear to play a role in the pathogenesis of a number of CNS disorders. For example, NTF expression is altered with brain trauma and seizure activity. We hypothesize that alterations in NTF activity during development are involved in the pathogenesis of schizophrenia; preliminary data presented at this meeting by Kaufmamr et al. are consistent with such a possibility. Brain abnormalities in schizophrenic patients am found prior to the illness and appear to correlate with clinical status. Suddath et al. working with twins discordant for schizophrenia find that increased VBR is almost In the hippocampus, without exception found in the ill twin. neuroimaging shows decreased hippocampal volumes in MRI
scans, and neuropathological studies reveal cellular disarray. To address the etiological role of NTFs in schizophrenia requires (I) identification of candidate NTFs that are altered in schizophrenic patients, as initiated by Kaufmamr et al. (2) Characterization of patterns of NTF expression during crucial periods of brain development. For example, both BDNF and Neurotrophin-3 have been localized to the midbrain, the location of most of the brain’s dopamine neurons and appear to exert strong trophic support; in target areas, such as the hippocampus, several NTFs are found including NGF, which exerts a trophic effect on cholinergic neurons, and could be. the factor identified by Kaufmann et al. (3) Further characterization of additional NTF effects on key populations of neurons. If NTF differences between control and schizophrenic brains are identified this should offer insight into the underlying pathology. Eventually, measurement of NTFs could be used clinically to inform treatment.
CHARACTERIZATION OF GLUTAMATE RECEPTOR SUBUNITS IN HUMAN POSTMORTEM BRAIN TISSUE FROM NORMAL, ALCOHOLIC, AND SCHIZOPHRENIC PATIENTS C.R. Breese, T.M. Bartell, S.W. Rogers, S. Leonard* Department of Pharmacology, C-268-7 I, University of Colorado Health Sciences Center, 4200 E. Ninth Ave., Denver, CO 80262, USA Antibodies to the functional AMPA (GluRl, GluR2, GluR3). and kainate binding sites (GluR5-7) were utilized as probes to characterize the glutamatergic receptors in human postmortem brain tissue from normal controls (n = 7). alcoholics (n = 5). and schizophrenics (n = 5). Antibodies were raised in rabbits from various rat receptor antigens expressed in fusion proteins in bacteria (Rogers, et al., J. Neurosci. 11:2713). Previous studies indicated that these antisera cross react with human brain tissue (Neurosci. Abs., 1992). Specific binding of antisera to the appropriate receptor subtypes were demonstrated by absorption of antisera with appropriate antigen, and antigen blots utilizing fusion proteins from the various receptor subtypes. Crude membrane fractions from postmortem brain tissue were fractionated by SDS-PAGE, transferred to nitrocellulose, and probed with antisera to various glutamatergic receptor subtypes in the cingulate, temporal cortex, hippocampus, and caudate. Our studies indicate, that in the brain regions examined, there were reductions in the apparent immunoreactivity of both AMPA and kainate receptor subtypes in most schizophrenics and some alcoholics; however, reductions were also observed in NCAM immunoreactivity, suggesting a possible neuronal loss in these samples. In addition, there was a high correlation between the loss of immunoreactivity of these antisera and the storage time of the tissue. There was no apparent alterations in immunoreactivity due to factors such as age, sex, smoking history or postmortem interval. These results suggest possible glutamatergic receptor alterations in the brains of schizophrenic and alcoholic patients.
8. Neurochemistryh4olecular Biology PLASMA AND PLATELETS GLUTAMATE LEVELS IN MAJOR PSYCHOSES AC. Altamura, M.C. Mauri, A. Ferrara, G. D’Andrea* Department of Psychiatry, University of Milan, 20122 Milan, Italy; *Department of Neurology, General Hospital Vicenza, Italy Excitatory aminoacids (EAA) in CNS, play an important role in neuronal plasticity, cell degeneration, and are also involved in Recently, a cognitive processes and memory acquisition. “glutamatergic theory” of schizophrenia has been envisaged where a failure of cortical glutamatergic projections modulating DA mesolimbic pathways has been hypothesized. 32 out-patients, diagnosed according to the DSM III-R as suffering from Schizophrenia (11 pt), Mood Disorders (15 pt), Anxiety Disorders (6 pt) and a control group (19 pt), entered into the study. All patients were off any psychotropic medication for at least 3 weeks. Plasma and platelet EAA determinations were carried out by means of a Millipore Waters HPLC system connected to a Perkin Elmer fluorescence spectrometer. Schizophrenic patients showed a trend towards an increase in glutamate plasma levels but it was statistically significant only in depressed patients. Glutamate platelet levels did not show any significant difference between patients and controls. The AA discuss the possible significance of these data in relation to the pathogenetic role of glutamate in Schizophrenia and Mood Disorders.
COULD ABERRANT NEUROTROPHIC ACTIVITY CAUSE SCHIZOPHRENIA? T. Anthony*, Stephen Rayport, Charles A. Kaufmann Donna
Department of Psychiatry, Columbia University; New York State Psychiatric Institute, 722 W. 168 St., New York, NY 10032, USA Alterations in neurotrophic factor (NTF) expression appear to play a role in the pathogenesis of a number of CNS disorders. For example, NTF expression is altered with brain trauma and seizure activity. We hypothesize that alterations in NTF activity during development are involved in the pathogenesis of schizophrenia; preliminary data presented at this meeting by Kaufmamr et al. are consistent with such a possibility. Brain abnormalities in schizophrenic patients am found prior to the illness and appear to correlate with clinical status. Suddath et al. working with twins discordant for schizophrenia find that increased VBR is almost In the hippocampus, without exception found in the ill twin. neuroimaging shows decreased hippocampal volumes in MRI
scans, and neuropathological studies reveal cellular disarray. To address the etiological role of NTFs in schizophrenia requires (I) identification of candidate NTFs that are altered in schizophrenic patients, as initiated by Kaufmamr et al. (2) Characterization of patterns of NTF expression during crucial periods of brain development. For example, both BDNF and Neurotrophin-3 have been localized to the midbrain, the location of most of the brain’s dopamine neurons and appear to exert strong trophic support; in target areas, such as the hippocampus, several NTFs are found including NGF, which exerts a trophic effect on cholinergic neurons, and could be. the factor identified by Kaufmann et al. (3) Further characterization of additional NTF effects on key populations of neurons. If NTF differences between control and schizophrenic brains are identified this should offer insight into the underlying pathology. Eventually, measurement of NTFs could be used clinically to inform treatment.
CHARACTERIZATION OF GLUTAMATE RECEPTOR SUBUNITS IN HUMAN POSTMORTEM BRAIN TISSUE FROM NORMAL, ALCOHOLIC, AND SCHIZOPHRENIC PATIENTS C.R. Breese, T.M. Bartell, S.W. Rogers, S. Leonard* Department of Pharmacology, C-268-7 I, University of Colorado Health Sciences Center, 4200 E. Ninth Ave., Denver, CO 80262, USA Antibodies to the functional AMPA (GluRl, GluR2, GluR3). and kainate binding sites (GluR5-7) were utilized as probes to characterize the glutamatergic receptors in human postmortem brain tissue from normal controls (n = 7). alcoholics (n = 5). and schizophrenics (n = 5). Antibodies were raised in rabbits from various rat receptor antigens expressed in fusion proteins in bacteria (Rogers, et al., J. Neurosci. 11:2713). Previous studies indicated that these antisera cross react with human brain tissue (Neurosci. Abs., 1992). Specific binding of antisera to the appropriate receptor subtypes were demonstrated by absorption of antisera with appropriate antigen, and antigen blots utilizing fusion proteins from the various receptor subtypes. Crude membrane fractions from postmortem brain tissue were fractionated by SDS-PAGE, transferred to nitrocellulose, and probed with antisera to various glutamatergic receptor subtypes in the cingulate, temporal cortex, hippocampus, and caudate. Our studies indicate, that in the brain regions examined, there were reductions in the apparent immunoreactivity of both AMPA and kainate receptor subtypes in most schizophrenics and some alcoholics; however, reductions were also observed in NCAM immunoreactivity, suggesting a possible neuronal loss in these samples. In addition, there was a high correlation between the loss of immunoreactivity of these antisera and the storage time of the tissue. There was no apparent alterations in immunoreactivity due to factors such as age, sex, smoking history or postmortem interval. These results suggest possible glutamatergic receptor alterations in the brains of schizophrenic and alcoholic patients.