- Email: [email protected]
Increase of glutamate dehydrogenase levels in frontal and cingulate cortex in schizophrenia
255
binding techniques. This study focuses on the CCKB receptor mRNA expression in cynomolgus monkey and human brain revealing implications for schizophrenia. We examined the monkey and human brain distribution of mRNAs encoding CCKB receptors compared with mRNA encoding CCK peptide using in situ hybridisation histochemistry. Monkey and human brain expression of CCKB receptor mRNA show preferentially cortical distribution, with laminar expression of CCKB receptor mRNA in the neocortex, hippocampus and cerebellar cortex. Low CCKB receptor mRNA levels are seen in subcortical structures such as the striatum, amygdala and claustrum. CCK peptide mRNA in monkey is more specifically distributed to neocortex and hippocampus, displaying laminar distribution. Lower levels are seen in the amygdala, claustrum and substantia nigra. The human brain distribution of mRNAs for CCKB receptors and CCK peptide, respectively, is similar to that of the cynomolgus monkey brain. Hybridisation to tissue sections of post-mortem frontal cortex of schizophrenics and matched controls (B.A. 10) revealed significant decrease of mRNAs for two splicing variants of the CCK B receptor in specific layers of the frontal cortex. This study demonstrates a highly preserved CCK system in brains of human and non-human primates displaying similarities with rodent data. New evidence is added for CCK involvement in schizophrenia. Thus CCKB receptor ligands should be studied more for implications in the treatment of schizophrenia.
many psychotic patients; reanalysing the data after identifying a 'psychosis' group of schizophrenics and psychotic bipolar patients indicated that both PV- and CB-IR neurons are diminished in the cortex in psychotic illness (p=0.029 and 0.023 respectively). The absence of any area-by-diagnosis interaction indicate that the effects are generalised across both cortical regions. These findings suggest selective deficits of GABAergic neurons to be related to psychotic illness, indicating a common cortical neuropathology, and conceivably aetiology, within this broad diagnostic group. We thank the Theodore and Vada Stanley Foundation for financial support and the Stanley Foundation Neuropathology Consortium for the supply of brain tissue.
B.220. INCREASE OF GLUTAMATE DEHYDROGENASE LEVELS IN FRONTAL AND CINGULATE CORTEX IN SCHIZOPHRENIA G . S h Burbaeva, M.S. Turishcheva, O.K. Savushkina, E.B. Tereshkina, I.S. B o k s h a
Laboratory of Neurochemistry, Mental Health Research Center, Zagorodnoe sh. 2-2 Moscow, 113152 Russia
B.219. SELECTIVE DEFICITS OF FRONTAL CORTICAL GABAERGIC NEURONAL SUBTYPES DEFINED BY CALCIUM BINDING PROTEINS IN PSYCHOTIC ILLNESS G.P. Reynolds, Z.J. Z h a n g , I. Patten, C.L. Beasley
Department of Biomedical Science, University of Sheffield, SheffieM SIO 2TN, UK There is substantial evidence for deficits of GABAergic neurons in the frontal cortex in schizophrenia. These GABAergic neurons can be subdivided into three groups determined by the calcium binding protein (CBP) present - parvalbumin (PV), calbindin (CB) and calretinin (CR). Following on from our observation of a deficit of frontal cortical PV-immunoreactive (PV-IR) cells in schizophrenia, we have undertaken a systematic study of all three CBPs in two frontal cortical regions (areas 9 and 46) in tissue from a wellcharacterised series of brains from patients with schizophrenia, bipolar disorder, unipolar depression and matched controls ( 15 in each group). Initial analysis confirmed a deficit of PV-IR neurons in schizophrenia relative to control subjects ( p = 0.021), not significant for CR. However, lower values were also seen for CB in schizophrenia (p=0.034), and a tendency for lower PV and CB in the bipolar group, which included
Disturbance in brain glutamate metabolism in schizophrenia could result from altered functioning of one of essential glutamate metabolizing enzymes, particularly glutamate dehydrogenase (GDH). Our investigation of normal human brain GDH revealed two isoenzymes. GDH-1 (presented by 56 and 58 kDa protein bands in SDS-electrophoresis in PAAG) and GDH-II (56kDa), which differ in hydrophobicity and thermostability. GDH activity and immunoreactivity of GDH-I in anterior and posterior cingulate cortex and frontal cortex from left hemispheres of control group (9 cases) and schizophrenic patients (9 cases), diagnosed premortem according to ICD-10 criteria, were examined. GDH activity was evaluated by routine method. GDH-I immunoreactivity was estimated quantitatively by immunoblotting-ECL using polyclonal antibodies. Substantial increase of GDH activity in frontal cortex and in posterior cingulate cortex of schizophrenics compared to controls (p < 0.01 ) was observed, in anterior cingulate cortex elevation was less distinct (p=0.05). In parallel, significant elevation of immunoreactivity level of GDH-I in schizophrenics versus controls was revealed in frontal cortex and posterior cingulate cortex (both protein bands, p<0.01), whereas in anterior cingulate cortex only one band (56 kDa) intensity increase was significant (p<0.05). It may be supposed that elevation of GDH activity is due to increase of GDH protein content (at least one of forms). Thus, altered functioning of one of the glutamate metabolism key enzymes GDH takes place in schizophrenic brain. (Supported by the Theodore and Vada Stanley Foundation).
binding techniques. This study focuses on the CCKB receptor mRNA expression in cynomolgus monkey and human brain revealing implications for schizophrenia. We examined the monkey and human brain distribution of mRNAs encoding CCKB receptors compared with mRNA encoding CCK peptide using in situ hybridisation histochemistry. Monkey and human brain expression of CCKB receptor mRNA show preferentially cortical distribution, with laminar expression of CCKB receptor mRNA in the neocortex, hippocampus and cerebellar cortex. Low CCKB receptor mRNA levels are seen in subcortical structures such as the striatum, amygdala and claustrum. CCK peptide mRNA in monkey is more specifically distributed to neocortex and hippocampus, displaying laminar distribution. Lower levels are seen in the amygdala, claustrum and substantia nigra. The human brain distribution of mRNAs for CCKB receptors and CCK peptide, respectively, is similar to that of the cynomolgus monkey brain. Hybridisation to tissue sections of post-mortem frontal cortex of schizophrenics and matched controls (B.A. 10) revealed significant decrease of mRNAs for two splicing variants of the CCK B receptor in specific layers of the frontal cortex. This study demonstrates a highly preserved CCK system in brains of human and non-human primates displaying similarities with rodent data. New evidence is added for CCK involvement in schizophrenia. Thus CCKB receptor ligands should be studied more for implications in the treatment of schizophrenia.
many psychotic patients; reanalysing the data after identifying a 'psychosis' group of schizophrenics and psychotic bipolar patients indicated that both PV- and CB-IR neurons are diminished in the cortex in psychotic illness (p=0.029 and 0.023 respectively). The absence of any area-by-diagnosis interaction indicate that the effects are generalised across both cortical regions. These findings suggest selective deficits of GABAergic neurons to be related to psychotic illness, indicating a common cortical neuropathology, and conceivably aetiology, within this broad diagnostic group. We thank the Theodore and Vada Stanley Foundation for financial support and the Stanley Foundation Neuropathology Consortium for the supply of brain tissue.
B.220. INCREASE OF GLUTAMATE DEHYDROGENASE LEVELS IN FRONTAL AND CINGULATE CORTEX IN SCHIZOPHRENIA G . S h Burbaeva, M.S. Turishcheva, O.K. Savushkina, E.B. Tereshkina, I.S. B o k s h a
Laboratory of Neurochemistry, Mental Health Research Center, Zagorodnoe sh. 2-2 Moscow, 113152 Russia
B.219. SELECTIVE DEFICITS OF FRONTAL CORTICAL GABAERGIC NEURONAL SUBTYPES DEFINED BY CALCIUM BINDING PROTEINS IN PSYCHOTIC ILLNESS G.P. Reynolds, Z.J. Z h a n g , I. Patten, C.L. Beasley
Department of Biomedical Science, University of Sheffield, SheffieM SIO 2TN, UK There is substantial evidence for deficits of GABAergic neurons in the frontal cortex in schizophrenia. These GABAergic neurons can be subdivided into three groups determined by the calcium binding protein (CBP) present - parvalbumin (PV), calbindin (CB) and calretinin (CR). Following on from our observation of a deficit of frontal cortical PV-immunoreactive (PV-IR) cells in schizophrenia, we have undertaken a systematic study of all three CBPs in two frontal cortical regions (areas 9 and 46) in tissue from a wellcharacterised series of brains from patients with schizophrenia, bipolar disorder, unipolar depression and matched controls ( 15 in each group). Initial analysis confirmed a deficit of PV-IR neurons in schizophrenia relative to control subjects ( p = 0.021), not significant for CR. However, lower values were also seen for CB in schizophrenia (p=0.034), and a tendency for lower PV and CB in the bipolar group, which included
Disturbance in brain glutamate metabolism in schizophrenia could result from altered functioning of one of essential glutamate metabolizing enzymes, particularly glutamate dehydrogenase (GDH). Our investigation of normal human brain GDH revealed two isoenzymes. GDH-1 (presented by 56 and 58 kDa protein bands in SDS-electrophoresis in PAAG) and GDH-II (56kDa), which differ in hydrophobicity and thermostability. GDH activity and immunoreactivity of GDH-I in anterior and posterior cingulate cortex and frontal cortex from left hemispheres of control group (9 cases) and schizophrenic patients (9 cases), diagnosed premortem according to ICD-10 criteria, were examined. GDH activity was evaluated by routine method. GDH-I immunoreactivity was estimated quantitatively by immunoblotting-ECL using polyclonal antibodies. Substantial increase of GDH activity in frontal cortex and in posterior cingulate cortex of schizophrenics compared to controls (p < 0.01 ) was observed, in anterior cingulate cortex elevation was less distinct (p=0.05). In parallel, significant elevation of immunoreactivity level of GDH-I in schizophrenics versus controls was revealed in frontal cortex and posterior cingulate cortex (both protein bands, p<0.01), whereas in anterior cingulate cortex only one band (56 kDa) intensity increase was significant (p<0.05). It may be supposed that elevation of GDH activity is due to increase of GDH protein content (at least one of forms). Thus, altered functioning of one of the glutamate metabolism key enzymes GDH takes place in schizophrenic brain. (Supported by the Theodore and Vada Stanley Foundation).