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Abnormal neurochemical asymmetry in the temporal lobe of schizophrenia
Prog Neuro-Psychopharmacol. & Biol. Psychtat. 2001, Vol 25, pp. 867--877 Copyright © 2001 Elsevier Sctence Inc Printed m the USA. All rights reserved 0278-5846 / 01/S--see front matter ELSEVIER
PII: S0278-5846(0
I)00149-X
ABNORMAL NEUROCHEMICAL ASYMMETRY IN T H E TEMPORAL LOBE OF SCHIZOPHRENIA
OSAMU SHIRAKAWA, NOBORU KITAMURA, XIAN-HAO LIN, TAKESHI HASHIMOTO and KIYOSHI MAEDA
Department of Psychiatry and Neurology, Kobe University School of Medicine, Kobe, Japan
(Final form, April 2001)
Contents Abstract Introduction Abnormal Neuroanatomical Asymmetries in the Schizophrenic Brain Abnormal Neurochemical Asymmetries in the Temporal Lobe of the Schizophrenic Brain 4. 5-HT2A Receptor-Mediated Signal Transduction and Schizophrenia 4.1 5-HT2A Receptor-Mediated Signal Transduction in the STG of Schizophrenic Brain 4.2 Abnormal Asymmetry of 5-HT2A Receptor-Mediated Signal Transduction in the STG of Schizophrenic Brain 5. Conclusions Acknowledgements References 1. 2. 3.
Abstract Shirakawa, Osamu, Noboru Kitamura, Xian-Hao Lin, Takeshi Hashimoto and Kiyoshi Maeda: Abnormal Neurochemical Asymmetry in the Temporal Lobe of Schizophrenia.
Prog JVeuro-Psychopharmacol.& Biol. Psychiat.2 0 0 1 , 867
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1. Neuroanatomical asymmetries are known to be present in the human brain, and loss of reversal of these asymmetries, particularly through changes in the left temporal lobe, have been found in the brains of patients with schizophrenia. 2. In addition to disturbed neuroanatomical asymmetries, disturbed neurochemical asymmetries have also been reported in the brains of patients with schizophrenia. However, in the temporal lobe, the laterality of most of these neurochemical changes has not been specifically evaluated. Few neurochemical studies have addressed leftright differences in the superior temporal gyrus (STG). 3. A deteriorated serotonin2A receptor-G protein qct (Gqcz)-phosphoinositide-specific phospholipase C 131(PLC 131) cascade has been found in the left, but not right, STG of patients with schizophrenia. 4. Not only neuroanatomical but also neurochemical evidence supports the loss or reversal of normal asymmetry of the temporal lobe in schizophrenia, which might be due to a disruption of the neurodevelopmental processes involved in hemispheric lateralization. Keywords: asymmetry, lateralization, neuroanatomy, neurochemistry, planum temporale, schizophrenia, serotonin, superior temporal gyrus.
Abbreviations: G protein qa (Gqct), phosphoinositide-specific phospholipase C 131 (PLC 131), planum temporale (PT), serotonin (5-HT), superior temporal gyrus (STG).
1. Intr0du~tion
Cerebral lateralization, particularly for functions underlying language and hand preference, is a unique feature of the human brain, although the existence of cerebral lateralization at the structural and functional levels also has been demonstrated in a range of non-human species. One of the most marked neuroanatomical asymmetries in the human brain has been identified in the planum temporale (PT) (Petty 1999, Shapleske et al. 1999). The neuroanatomical asymmetry of the PT has been associated with the localization of language function and handedness. Abnormalities in cerebral asymmetry have been found in the brains of patients with schizophrenia (Cowell et a1.1999, Petty 1999). Some of the most common findings are
Neurochemical asymmetry in schizophrenic temporal lobe
869
decreases in the size of structures within the left temporal lobe, including the PT and the superior temporal gyrus (STG).
Reversals or losses of normal asymmetry of the PT and
the STG have been reported in the brains of patients with schizophrenia (Crow 1990, DeLisi et al. 1994, Petty et al. 1995, Barta et al. 1997, Frangou et al. 1997, Kwon et al. 1999). The association of neuroanatomical and neurochemical asymmetries has received increasing attention.
Although abnormal neurochemical asymmetries have been reported
in the brains of patients with schizophrenia, there have been few neurochemical studies on left-right differences in the PT and the STG. Recently there has been growing interest in the potential involvement of serotonin (5-HT) in both the pathophysiology of schizophrenia and its role in mediating the effects of antipsychotic drugs.
A common feature of "atypical" antipsychotic drugs is their
preferential blockade of 5-HT2A receptors.
The 5-HT2A receptor is one of the
neurotransmitter receptors coupled with the G protein qct (Gqct)-phosphoinositide-specific phospholipase C [3I(PLC 131) cascade (Roth et al. 1998, Barnes and Sharp 1999). Disturbances in this system have been found in the left, but not right, STG of schizophrenic patients (Nishino et al. 1993, Kitamura et al. 1998, Yang et al. 1998, Lin et al. 1999). Based on these results, the authors would like to consider the links between neuroanatomical changes and neurochemical pathophysiology in schizophrenia.
2. Abnormal Neuroanatomical Asvmmetries in the Schizophrenic Brain
Neuroimaging studies and postmortem studies have provided evidence of reversal or loss of the normal structural asymmetry of the schizophrenic brain (Cowell et al. 1999, Petty 1999). Some of the strongest evidence of disturbances of neuroanatomical asymmetries have been the finding of reductions in the size of structures within the left temporal lobe of the schizophrenic brain, including the STG (Barta et al. 1990, Shenton et al. 1992, Highley et al. 1999) and the PT (Hoff et al. 1992, Rossi et al. 1992, Bilder et al. 1994, Petty et al. 1995, Falkai et al. 1995). Notably, the left-sided decreases in the STG and the PT, which resulted in the reversal or loss of the normal asymmetry (Crow 1990,
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Rossi et al. 1992, Delisi et al. 1994, Petty et al. 1995, Barta et al. 1997, Frangou et al. 1997), were found to correlate with the severity of auditory hallucinations (Barta et al. 1990) and thought disorder (Shenton et al. 1992, Petty et al. 1995).
A reversal or loss of
the normal asymmetry of these regions in schizophrenia appears to be disease-specific and not related to antipsychotic treatment (Barta et al. 1997, Pearlson et al. 1997, Keshavan et al. 1998, Hirayasu et al. 1998).
3. Abnormal Neurochemical Asymmetries in the Temooral Lobe of the Schizot~hrenic Brain
Although left-sided limbic abnormalities in dopaminergic, GABAergic, and glutamatergic mechanisms have been found in the schizophrenic brain (Kerwin et al. 1988, Deakin et al. 1989, Reynolds 1983, Reynolds et al. 1990), there have been few systematic studies into left-right neurochemical differences in the temporal lobe of the schizophrenic brain. The links between the neurochemical abnormalities and the neuroanatomical changes in the temporal lobe remain to be unraveled. Recently our group found changes of the proteins involved in neurotransmitter signaling (Gict, Goa, Gqa, Protein kinase A) and a cytoskeletal protein (a-fodrin), in the left but not right STG (Nishino et al. 1993, Kitamura et al. 1998, Yang et a1.1998, Lin et al. 1999).
4. 5-HT2A Receotor-Mediated Signal Transduction and Schizoohrenia
Recently the role of 5-HT in antipsychotic action has been receiving much attention, mainly because "atypical" antipsychotic drugs are potent 5-HT2A antagonists. The 5HT2A receptor is highly enriched in the cerebral cortex and is one of the neurotransmitter receptors coupled with the Gqa-PLC 131 cascade (Roth et al. 1998, Barnes and Sharp 1999). It is likely that 5-HT2A receptors play crucial roles in the modulation of perception, cognition, and emotion, although the role of 5-HT2A receptors in the pathogenesis of
Neurochemical asymmetry in schizophrenic temporal lobe
871
schizophrenia is not clear. A decreased density of 5-HT2A receptors in various cortical areas of schizophrenic brains has been reported (Mita et al. 1986, Arora and Meltzer 1991, Hashimoto et al. 1993, Burnet et al. 1996, Gurevich and Joyce 1997).
This change might be at least in part
related to antipsychotic treatment (Gurevich and Joyce 1997).
As shown in Fig 1 and 2,
the authors found abnormalities in the 5-HT2A receptor-Gq~-PLC [31 cascade in the STG of schizophrenic patients, in which morphometfic abnormalities in lateralization have been repeatedly observed by neuroimaging and postmortem studies (Cowell et al. 1999, Petty 1999).
4.1 5-HT2A Receptor-Mediated Signal Transduction in the STG of the Schizoohrenic Brain (Fig 1)
In the left and fight STG of schizophrenic patients, the 5-HT2A receptors labeled by 3H-ketansefin are significantly decreased.
In schizophrenic patients, Gqa
immunoreactivities are decreased in the left STG, while those in the fight STG are not changed.
PLC 131 immunoreactivities are decreased in the left STG of schizophrenic
patients.
There is no difference in PLC 131 immunoreactivities in the fight STG between
schizophrenic patients and controls.
Thus, in the left STG of schizophrenic patients, all
of the markers of 5-HT2A receptor-mediated signal transduction are decreased, indicating a deteriorated 5-HT2A receptor-Gqot-PLC 131 cascade.
4.2 Abnormal Asvmmetrv of 5HT2A Receotor-Mediated Si~nalTransduction in the STG of the Schizonhrenic Brain (Fig 2)
The density of 5-HT2A receptors in the STG shows no left-fight asymmetry in the schizophrenic patients or controls. In the controls, the Gqa immunoreactivity shows leftsided dominant lateralization, while the PLC ~ 1 immunoreactivity tends to show a leftsided dominant lateralization.
In the schizophrenic patients, there is fight-sided
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Fig 1. Changes of 5HT2A receptor density, Gqa immunoreactivity and PLC 131 immunoreactivity in the ST(3 from controls and schizophrenics. Values are means ± S.E. The left and fight STGs of postmortem brains were obtained from 13 schizophrenic subjects (8 men and 5 women, mean age 64.5 +15.0 yr (S.D.)) and 13 control subjects (8 men and 5 women, mean age 54.0 ± 18.2). 3H-ketanserin (lnM) was used to identify 5-HT2A receptors. Nonspecific binding was determined in the presence of I gM pipanperone. Gqa and PLC ~ 1 were immunoquantified by Western blot analysis using specific antibodies. Densitometfic readings of bands in the immunoblots were expressed as a percentage of the average values in the left ST(} of the controls. *p<0.05, **p<0.005 (Student's t-test)
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Fig 2. Left-to-right ratios of 5HT2A receptor density, Gqa immunoreactivity and PLC ~1 immunoreactivity in the STG in controls (O) and schizophrenics (,). Values are means ± S.E. Ratio of left to fight is the ratio of the individual's 5HT2A Receptor Density, Gqa and PLC 131. Immunoreactivities on the left side to those on the right side. Points above and below dotted line indicate left and fight dominance, respectively. *p<0.005, **p<0.0005 (Student's t-test)
Neurochemical asymmetry in schizophrenic temporal lobe
dominance in the Gqct and PLC [31 immunoreactivities.
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Thus, loss or reversal of normal
asymmetry of the Gqc~ and PLC 131 immunoreaetivities is found in the STG of schizophrenic patients.
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Normal brain development leads to anatomical asymmetries under strong genetic control (Geschwind and Galaburda, 1985).
One of the key anatomical changes in
schizophrenia appears to be a loss or even reversal of the asymmetries of the STG or the PT.
Compared with the
neuroanatomical studies, most of the neurochemical studies
have not specifically evaluated laterality.
A deteriorated 5-HT2A receptor-Gqct-PLC ~ 1
cascade in the left hut not right STG of patients with schizophrenia provides information about the relationship between neuroanatomical and neurochemical asymmetries in the temporal lobe of schizophrenia.
Further studies that confirm left-side specific
neurochemical changes, or a loss or reversal of the neurochemical normal asymmetry in the STG or the PT of the schizophrenic brain could clarify the correlation between structural and functional abnormalities in the temporal lobe of schizophrenia.
Such
studies would support the hypothesis that there is a disruption of neurodevelopmental processes involved in hemispheric lateralization which may be genetically controlled.
Acknowled~ementq
This work was supported by a grant from the Ministry of Education, Science, Culture, and Sports and a Research Grant (8B-l) for Nervous and Mental Disorders from the Ministry of Health and Welfare, Japan. The authors also thank Mr. J. Raymond for a critical reading of the manuscript.
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ARORA, R.C. and MELTZER, H.Y. (1991) Serotonin (5-HT2) receptor binding in the frontal cortex of schizophrenic patients. J. Neu. Transm. 85:19-29. BARNES, N.M. and SHARP, T. (1999) A review of central 5-HT receptors and their function. Neuropharmacol. 38: 1083-1152. BARTA, P.E., PEARLSON, G.D., POWERS, R.E., RICHARDS, S.S. and TUNE, L.E. (1990) Auditory hallucinations and smaller superior temporal gyral volume in schizophrenia. Am. J. Psychiat. 147:1457-1462. BARTA, P.E., PEARLSON, G.D., BRILL, L.B., ROYALL, R., MCGILCHRIST, I.K., PULVER, A.E., POWERS, R.E., CASANOVA, M.F., TIEN, A.Y., FRANGOU, S. and PETTY, R.G. (1997) Planum temporale asymmetry reversal in schizophrenia: Replications and relationship to gray matter abnormalities. Am. J. Psychiat. 154: 661667. BILDER, R.M., WU, H., BOGERTS, B., DEGREEF, G., ASHTARI, M., ALVIR, J.M., SNYDER, P.J. and LIEBERMAN, J.A. (1994) Absence of regional hemispheric volume asymmetries in first-episode schizophrenia. Am. J. Psychiat. 151:1437-1447 BURNET, P.W., EASTWOOD, S.L. and HARRISON, P.J. (1996) 5-HT1A and 5-HT2A receptor mRNAs and binding sites densities are differentially altered in schizophrenia. Neuropsychopharmacol.15: 442-455. COWELL, P.E. FITCH, R.H. and DENENBERG, V.H. (1999) relevance to schizophrenia. Schizophr. Bull. 25 : 41-62.
Laterality in animals:
CROW, T.J. (1990) Temporal lobe asymmetries as the key to the etiology of schizophrenia. Schizophr. Bull. 16: 433-443. DEAKIN, J.F., SLATER,P., SIMPSON, M.D., GILCHRIST, A.C., SKAN, W.J., ROYSTON, M.C., REYNOLDS, G.P. and CROSS, A.J. (1989) Frontal cortical and left temporal glutamatergic dysfunction in schizophrenia. J. Neurochem. 52:1781-6. DELISI, L.E., HOFF, A.L., NEALE, C. and KUSHNER, M. (1994) Asymmetries in the superior temporal lobe in male and female first-episode schizophrenic patients: Measures of the planum temporale and superior temporal gyms by MRI. Schizophr. Res. 12: 19-28. FALKAI, P., BOGERTS, B., SCHNEIDER, T., GREVE, B., PFEIFFER, U., PILZ, K., GONSIORZCYK, C., MAJTENYI, C. and OVARY, I. (1995) Disturbed planum temporale asymmetry in schizophrenia. A quantitative post-mortem study. Schizophr. Res. 14:161-176. FRANGOU, S., SHARMA, T., SIGMUDSSON, T., BARTA, P., PEARLSON, G. and MURRAY, R.M. (1997) The Maudsley Family Study, 4: Normal planum temporale asymmetry in familial schizophrenia. A volumetric MRI study. Br. J. Psychiat. 170: 328-333.
Neurochemical asymmetry in schizophrenic temporal lobe
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GESCHWIND, N. and GALABUEDA, A.M. (1985) Cerebral lateralization, biological mechanism, associations, and pathology: I. A hypothesis and a program for research. Archives of Neurol. 42: 428-459. GUREVICH, E.V. and JOYCE, J.N. (1997) Alterations in the cortical serotonergic system in schizophrenia: A postmortem study. Biol. Psychiat. 42:529-545. HASHIMOTO, T., KITAMURA, K., KAJIMOTO, Y., SHIRAI, Y., SHIRAKAWA, O., MITA, T., NISHINO, N. and TANAKA, C. (1993) Differential changes in serotonin 5-HT 1A and 5-HT2 receptor binding in patients with chronic schizophrenia. Psychopharmacol. 112: $35-$39. HIGHLEY, J.R., MCDONALD, B.B., WALKER, M.A., ESIRI, M.M. and CROW, T.J. (2000) Schizophrenia and temporal lobe asymmetry A post-mortem stereological study of tissue volume. Br. J. Psychiat.175: 127-134. HIRAYASU, Y., SHENTON, M.E., SALISBURY, D.F., DICKEY, C.C., FISCHER, I.A., MAZZONI, P., KISLER, T., ARAKAKI, H., Kwon, J.S., ANDERSON, J.E., YURGELUN-Todd, D., TOHEN, M. and MCCARLEY, R.W. (1998) Lower left temporal lobe MRI volumes in patients with first-episode schizophrenia compared with psychotic patients with first-episode affective disorder and normal subjects. Am. J. Psychiat. 155:1384-1391. HOFF, A.L., RIORDAN, H., O'DONNELL, D., STRITZKE, P., NEALE, C., BOCCIO, A., ANAND, A.K. and DELISI, L.E. (1992) Anomalous lateral sulcus asymmetry and cognitive function in first-episode schizophrenia. Schizophr. Bull. 18:257-272. KERWIN, R.W., PATEL, S., MELDRUM, B.S., CZUDEK, C. and REYNOLDS, G.P. (1988)Asymmetrical loss of glutamate receptor subtype in left hippocampus in schizophrenia. Lancet I (8585): 583-584. KESHAVAN, M.S., HAAS, G.L., KAHN, C.E., AGUILAR, E., DICK, E.L., SCHOOLER, N.R., SWEENEY, J.A. and PE'Iq'EGREW, J.W. (1998) Superior temporal gyms and the course of early schizophrenia: progressive, static, or reversible? J. Psychiatr. Res. 32:161-167. KITAMURA, N., NISHINO, N., HASHIMOTO, T., KAJIMOTO, Y., SHIRAI, Y., MURAKAMI, N., YANG, C.-Q., LIN, X.-H., YAMAMOTO, H., NAKAI, T., MITA, T., KOMURE, O., SHIRAKAWA, O. and NAKAI, H. (1998) Asymmetrical changes in the fodrin _ subunit in the superior temporal cortices in schizophrenia. Biol. Psychiat. 43: 254-262. KWON, J.S., MCCARLEY, R.W., HIRAYASU, Y., ANDERSON, J.E., FISCHER, I.A., KIKINIS, R., JOLESZ, F.A. and SHENTON, M.E. (1999) Left planum temporale volume reduction in schizophrenia. Arch. Gen. Psychiat. 56:142-148. LIN, X.-H., KITAMURA, N., HASHIMOTO, T., SHIRAKAWA, O. and MAEDA, K. (1988) Opposite Changes in Phosphoinositide-specific Phospholipase C in the Left Prefrontal and Superior Temporal Cortex of Patients with Chronic Schizophrenia. Biol. Psychiatry. 46:1665-1671.
876
O. S h i r a k a w a et aL
MITA, T., HANADA, S., NISHINO, N., KUNO, T., NAKAI, H., YAMADORI, T., MIZOI, Y. and TANAKA, C. (1986) Decreased serotonin $2 and increased dopamine D2 receptors in chronic schizophrenics. Biol Psychiat. 21:1407-1414. NISHINO, O., KITAMURA, N., HASHIMOTO, T., KAJIMOTO, Y., SHIRAI, Y., MURAKAMI, N., NAKAI, T., KOMURE, O., SHIRAKAWA, O., MITA, T. and NAKAI, H. (1993) Increase in [3H]cAMP binding sites and decrease Gict and Goa immunoreactivities in left temporal cortices from patients with schizophrenia. Brain Res. 615: 41-49. PEARLSON, G.D., BARTA, P.E., POWERS, R.E., MENON, R.R., RICHARDS, S.S., AYLWARD, E.H., FEDERMAN, E.B., CHASE, G,A., PETTY, R.G. and TIEN, A.Y. (1988)Ziskind-Somerfeld Research Award 1996. Medial and superior temporal gyral volumes and cerebral asymmetry in schizophrenia versus bipolar disorder. Biol. Psychiat. 41:1-14. PETTY, R.G., BARTA, P.E., PEARL,SON, G.D., MCGILCHIRIST, I.K., LEWIS, R.W., TIEN, A.Y., PULVER, A., DARRELL VAUGHN, D., CASANOVA, M.F. and POWERS, R.E. (1995) Reversal of asymmetry of the planum temporale in schizophrenia. Am. J. Psychiat. 152:715-721. PETTY, R.G. (1999) Structural asymmetries of the human brain and their disturbance in schizophrenia. Schizophr. Bull. 2: 121-139. REYNOLDS, G.P. (1983) Increased concentrations and lateral asymmetry of amygdala dopamine in schizophrenia. Nature 305(5935k527-529. REYNOLDS, G.P., CZUDEK, C. and ANDREWS, H.B. (1990) Deficit and hemispheric asymmetry of GABA uptake sites in the hippoeampus in schizophrenia. Biol. Psychiat. 27:1038-44. ROSSI, A., STRATTA, P., MATTEI, P., CUPILLARI, M., BOZZAO, A., GALLUCCI, M. and CASACCHIA, M. (1992) Planum temporale in schizophrenia: A magnetic resonance study. Schizophr. Res. 7:19-22. ROTH, B.L., BERRY, S.A., KROEZE, W.K., WILLINS, D.L. and KRISTIANSEN, K. (1988)Serotonin 5-HT2A receptors: Molecular Biology and Mechanisms of Regulation. Crit. Rev. in Neurobiol. 12 : 319-338. SHAPLESKE, J., ROSSELL, S.L., WOODRUFF, P.W.R. and DAVID, A.S. (1999) The planum temporale: a systematic,quantitative review of its structural, functional and clinical significance. Brain Res. Rev. 29: 26-49. SHENTON, M.E.; KIKININS, R., JOLESZ, F.A., POLLACK, S.D., LEMAY, M., WIBLE, C.G., HOKAMA, H., MERTIN, J., METCALF, D., COLEMAN, M. and MCCARLEY, R.W. (1992) Abnormalities of the left temporal lobe and thought disorder in schizophrenia: A quantitative magnetic resonance imaging study. New Eng. J. Med. 327:604-612. YANG, C.-Q., KITAMURA, N., NISHINO, N., SHIRAKAWA, O. and NAKAI, H. (1988) Isotype-specific G protein abnormalities in the left superior temporal cortex
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and limbic structures of patients with chronic schizophrenia. Biol. Psychiat. 43: 12-19.
Inquiries and reprint requests should be addressed to:
Osamu Shirakawa, M.D., Ph.D., Department of Psychiatry and Neurology, Kobe University School of Medicine, 7-5-1 Kusunoki-cho Chuo-Ku Kobe 650-0017, Japan TEL: +81-78-382-6065 FAX: +81-78-382-6079
PII: S0278-5846(0
I)00149-X
ABNORMAL NEUROCHEMICAL ASYMMETRY IN T H E TEMPORAL LOBE OF SCHIZOPHRENIA
OSAMU SHIRAKAWA, NOBORU KITAMURA, XIAN-HAO LIN, TAKESHI HASHIMOTO and KIYOSHI MAEDA
Department of Psychiatry and Neurology, Kobe University School of Medicine, Kobe, Japan
(Final form, April 2001)
Contents Abstract Introduction Abnormal Neuroanatomical Asymmetries in the Schizophrenic Brain Abnormal Neurochemical Asymmetries in the Temporal Lobe of the Schizophrenic Brain 4. 5-HT2A Receptor-Mediated Signal Transduction and Schizophrenia 4.1 5-HT2A Receptor-Mediated Signal Transduction in the STG of Schizophrenic Brain 4.2 Abnormal Asymmetry of 5-HT2A Receptor-Mediated Signal Transduction in the STG of Schizophrenic Brain 5. Conclusions Acknowledgements References 1. 2. 3.
Abstract Shirakawa, Osamu, Noboru Kitamura, Xian-Hao Lin, Takeshi Hashimoto and Kiyoshi Maeda: Abnormal Neurochemical Asymmetry in the Temporal Lobe of Schizophrenia.
Prog JVeuro-Psychopharmacol.& Biol. Psychiat.2 0 0 1 , 867
2 5 , p p . 8 6 7 - - 8 7 7 . ~ 2 0 0 1 E l s e v i e r S c i e n c e Inc.
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1. Neuroanatomical asymmetries are known to be present in the human brain, and loss of reversal of these asymmetries, particularly through changes in the left temporal lobe, have been found in the brains of patients with schizophrenia. 2. In addition to disturbed neuroanatomical asymmetries, disturbed neurochemical asymmetries have also been reported in the brains of patients with schizophrenia. However, in the temporal lobe, the laterality of most of these neurochemical changes has not been specifically evaluated. Few neurochemical studies have addressed leftright differences in the superior temporal gyrus (STG). 3. A deteriorated serotonin2A receptor-G protein qct (Gqcz)-phosphoinositide-specific phospholipase C 131(PLC 131) cascade has been found in the left, but not right, STG of patients with schizophrenia. 4. Not only neuroanatomical but also neurochemical evidence supports the loss or reversal of normal asymmetry of the temporal lobe in schizophrenia, which might be due to a disruption of the neurodevelopmental processes involved in hemispheric lateralization. Keywords: asymmetry, lateralization, neuroanatomy, neurochemistry, planum temporale, schizophrenia, serotonin, superior temporal gyrus.
Abbreviations: G protein qa (Gqct), phosphoinositide-specific phospholipase C 131 (PLC 131), planum temporale (PT), serotonin (5-HT), superior temporal gyrus (STG).
1. Intr0du~tion
Cerebral lateralization, particularly for functions underlying language and hand preference, is a unique feature of the human brain, although the existence of cerebral lateralization at the structural and functional levels also has been demonstrated in a range of non-human species. One of the most marked neuroanatomical asymmetries in the human brain has been identified in the planum temporale (PT) (Petty 1999, Shapleske et al. 1999). The neuroanatomical asymmetry of the PT has been associated with the localization of language function and handedness. Abnormalities in cerebral asymmetry have been found in the brains of patients with schizophrenia (Cowell et a1.1999, Petty 1999). Some of the most common findings are
Neurochemical asymmetry in schizophrenic temporal lobe
869
decreases in the size of structures within the left temporal lobe, including the PT and the superior temporal gyrus (STG).
Reversals or losses of normal asymmetry of the PT and
the STG have been reported in the brains of patients with schizophrenia (Crow 1990, DeLisi et al. 1994, Petty et al. 1995, Barta et al. 1997, Frangou et al. 1997, Kwon et al. 1999). The association of neuroanatomical and neurochemical asymmetries has received increasing attention.
Although abnormal neurochemical asymmetries have been reported
in the brains of patients with schizophrenia, there have been few neurochemical studies on left-right differences in the PT and the STG. Recently there has been growing interest in the potential involvement of serotonin (5-HT) in both the pathophysiology of schizophrenia and its role in mediating the effects of antipsychotic drugs.
A common feature of "atypical" antipsychotic drugs is their
preferential blockade of 5-HT2A receptors.
The 5-HT2A receptor is one of the
neurotransmitter receptors coupled with the G protein qct (Gqct)-phosphoinositide-specific phospholipase C [3I(PLC 131) cascade (Roth et al. 1998, Barnes and Sharp 1999). Disturbances in this system have been found in the left, but not right, STG of schizophrenic patients (Nishino et al. 1993, Kitamura et al. 1998, Yang et al. 1998, Lin et al. 1999). Based on these results, the authors would like to consider the links between neuroanatomical changes and neurochemical pathophysiology in schizophrenia.
2. Abnormal Neuroanatomical Asvmmetries in the Schizophrenic Brain
Neuroimaging studies and postmortem studies have provided evidence of reversal or loss of the normal structural asymmetry of the schizophrenic brain (Cowell et al. 1999, Petty 1999). Some of the strongest evidence of disturbances of neuroanatomical asymmetries have been the finding of reductions in the size of structures within the left temporal lobe of the schizophrenic brain, including the STG (Barta et al. 1990, Shenton et al. 1992, Highley et al. 1999) and the PT (Hoff et al. 1992, Rossi et al. 1992, Bilder et al. 1994, Petty et al. 1995, Falkai et al. 1995). Notably, the left-sided decreases in the STG and the PT, which resulted in the reversal or loss of the normal asymmetry (Crow 1990,
870
O. S h i r a k a w a et al.
Rossi et al. 1992, Delisi et al. 1994, Petty et al. 1995, Barta et al. 1997, Frangou et al. 1997), were found to correlate with the severity of auditory hallucinations (Barta et al. 1990) and thought disorder (Shenton et al. 1992, Petty et al. 1995).
A reversal or loss of
the normal asymmetry of these regions in schizophrenia appears to be disease-specific and not related to antipsychotic treatment (Barta et al. 1997, Pearlson et al. 1997, Keshavan et al. 1998, Hirayasu et al. 1998).
3. Abnormal Neurochemical Asymmetries in the Temooral Lobe of the Schizot~hrenic Brain
Although left-sided limbic abnormalities in dopaminergic, GABAergic, and glutamatergic mechanisms have been found in the schizophrenic brain (Kerwin et al. 1988, Deakin et al. 1989, Reynolds 1983, Reynolds et al. 1990), there have been few systematic studies into left-right neurochemical differences in the temporal lobe of the schizophrenic brain. The links between the neurochemical abnormalities and the neuroanatomical changes in the temporal lobe remain to be unraveled. Recently our group found changes of the proteins involved in neurotransmitter signaling (Gict, Goa, Gqa, Protein kinase A) and a cytoskeletal protein (a-fodrin), in the left but not right STG (Nishino et al. 1993, Kitamura et al. 1998, Yang et a1.1998, Lin et al. 1999).
4. 5-HT2A Receotor-Mediated Signal Transduction and Schizoohrenia
Recently the role of 5-HT in antipsychotic action has been receiving much attention, mainly because "atypical" antipsychotic drugs are potent 5-HT2A antagonists. The 5HT2A receptor is highly enriched in the cerebral cortex and is one of the neurotransmitter receptors coupled with the Gqa-PLC 131 cascade (Roth et al. 1998, Barnes and Sharp 1999). It is likely that 5-HT2A receptors play crucial roles in the modulation of perception, cognition, and emotion, although the role of 5-HT2A receptors in the pathogenesis of
Neurochemical asymmetry in schizophrenic temporal lobe
871
schizophrenia is not clear. A decreased density of 5-HT2A receptors in various cortical areas of schizophrenic brains has been reported (Mita et al. 1986, Arora and Meltzer 1991, Hashimoto et al. 1993, Burnet et al. 1996, Gurevich and Joyce 1997).
This change might be at least in part
related to antipsychotic treatment (Gurevich and Joyce 1997).
As shown in Fig 1 and 2,
the authors found abnormalities in the 5-HT2A receptor-Gq~-PLC [31 cascade in the STG of schizophrenic patients, in which morphometfic abnormalities in lateralization have been repeatedly observed by neuroimaging and postmortem studies (Cowell et al. 1999, Petty 1999).
4.1 5-HT2A Receptor-Mediated Signal Transduction in the STG of the Schizoohrenic Brain (Fig 1)
In the left and fight STG of schizophrenic patients, the 5-HT2A receptors labeled by 3H-ketansefin are significantly decreased.
In schizophrenic patients, Gqa
immunoreactivities are decreased in the left STG, while those in the fight STG are not changed.
PLC 131 immunoreactivities are decreased in the left STG of schizophrenic
patients.
There is no difference in PLC 131 immunoreactivities in the fight STG between
schizophrenic patients and controls.
Thus, in the left STG of schizophrenic patients, all
of the markers of 5-HT2A receptor-mediated signal transduction are decreased, indicating a deteriorated 5-HT2A receptor-Gqot-PLC 131 cascade.
4.2 Abnormal Asvmmetrv of 5HT2A Receotor-Mediated Si~nalTransduction in the STG of the Schizonhrenic Brain (Fig 2)
The density of 5-HT2A receptors in the STG shows no left-fight asymmetry in the schizophrenic patients or controls. In the controls, the Gqa immunoreactivity shows leftsided dominant lateralization, while the PLC ~ 1 immunoreactivity tends to show a leftsided dominant lateralization.
In the schizophrenic patients, there is fight-sided
872
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Fig 1. Changes of 5HT2A receptor density, Gqa immunoreactivity and PLC 131 immunoreactivity in the ST(3 from controls and schizophrenics. Values are means ± S.E. The left and fight STGs of postmortem brains were obtained from 13 schizophrenic subjects (8 men and 5 women, mean age 64.5 +15.0 yr (S.D.)) and 13 control subjects (8 men and 5 women, mean age 54.0 ± 18.2). 3H-ketanserin (lnM) was used to identify 5-HT2A receptors. Nonspecific binding was determined in the presence of I gM pipanperone. Gqa and PLC ~ 1 were immunoquantified by Western blot analysis using specific antibodies. Densitometfic readings of bands in the immunoblots were expressed as a percentage of the average values in the left ST(} of the controls. *p<0.05, **p<0.005 (Student's t-test)
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Fig 2. Left-to-right ratios of 5HT2A receptor density, Gqa immunoreactivity and PLC ~1 immunoreactivity in the STG in controls (O) and schizophrenics (,). Values are means ± S.E. Ratio of left to fight is the ratio of the individual's 5HT2A Receptor Density, Gqa and PLC 131. Immunoreactivities on the left side to those on the right side. Points above and below dotted line indicate left and fight dominance, respectively. *p<0.005, **p<0.0005 (Student's t-test)
Neurochemical asymmetry in schizophrenic temporal lobe
dominance in the Gqct and PLC [31 immunoreactivities.
873
Thus, loss or reversal of normal
asymmetry of the Gqc~ and PLC 131 immunoreaetivities is found in the STG of schizophrenic patients.
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Normal brain development leads to anatomical asymmetries under strong genetic control (Geschwind and Galaburda, 1985).
One of the key anatomical changes in
schizophrenia appears to be a loss or even reversal of the asymmetries of the STG or the PT.
Compared with the
neuroanatomical studies, most of the neurochemical studies
have not specifically evaluated laterality.
A deteriorated 5-HT2A receptor-Gqct-PLC ~ 1
cascade in the left hut not right STG of patients with schizophrenia provides information about the relationship between neuroanatomical and neurochemical asymmetries in the temporal lobe of schizophrenia.
Further studies that confirm left-side specific
neurochemical changes, or a loss or reversal of the neurochemical normal asymmetry in the STG or the PT of the schizophrenic brain could clarify the correlation between structural and functional abnormalities in the temporal lobe of schizophrenia.
Such
studies would support the hypothesis that there is a disruption of neurodevelopmental processes involved in hemispheric lateralization which may be genetically controlled.
Acknowled~ementq
This work was supported by a grant from the Ministry of Education, Science, Culture, and Sports and a Research Grant (8B-l) for Nervous and Mental Disorders from the Ministry of Health and Welfare, Japan. The authors also thank Mr. J. Raymond for a critical reading of the manuscript.
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O. S h i r a k a w a e t al.
ARORA, R.C. and MELTZER, H.Y. (1991) Serotonin (5-HT2) receptor binding in the frontal cortex of schizophrenic patients. J. Neu. Transm. 85:19-29. BARNES, N.M. and SHARP, T. (1999) A review of central 5-HT receptors and their function. Neuropharmacol. 38: 1083-1152. BARTA, P.E., PEARLSON, G.D., POWERS, R.E., RICHARDS, S.S. and TUNE, L.E. (1990) Auditory hallucinations and smaller superior temporal gyral volume in schizophrenia. Am. J. Psychiat. 147:1457-1462. BARTA, P.E., PEARLSON, G.D., BRILL, L.B., ROYALL, R., MCGILCHRIST, I.K., PULVER, A.E., POWERS, R.E., CASANOVA, M.F., TIEN, A.Y., FRANGOU, S. and PETTY, R.G. (1997) Planum temporale asymmetry reversal in schizophrenia: Replications and relationship to gray matter abnormalities. Am. J. Psychiat. 154: 661667. BILDER, R.M., WU, H., BOGERTS, B., DEGREEF, G., ASHTARI, M., ALVIR, J.M., SNYDER, P.J. and LIEBERMAN, J.A. (1994) Absence of regional hemispheric volume asymmetries in first-episode schizophrenia. Am. J. Psychiat. 151:1437-1447 BURNET, P.W., EASTWOOD, S.L. and HARRISON, P.J. (1996) 5-HT1A and 5-HT2A receptor mRNAs and binding sites densities are differentially altered in schizophrenia. Neuropsychopharmacol.15: 442-455. COWELL, P.E. FITCH, R.H. and DENENBERG, V.H. (1999) relevance to schizophrenia. Schizophr. Bull. 25 : 41-62.
Laterality in animals:
CROW, T.J. (1990) Temporal lobe asymmetries as the key to the etiology of schizophrenia. Schizophr. Bull. 16: 433-443. DEAKIN, J.F., SLATER,P., SIMPSON, M.D., GILCHRIST, A.C., SKAN, W.J., ROYSTON, M.C., REYNOLDS, G.P. and CROSS, A.J. (1989) Frontal cortical and left temporal glutamatergic dysfunction in schizophrenia. J. Neurochem. 52:1781-6. DELISI, L.E., HOFF, A.L., NEALE, C. and KUSHNER, M. (1994) Asymmetries in the superior temporal lobe in male and female first-episode schizophrenic patients: Measures of the planum temporale and superior temporal gyms by MRI. Schizophr. Res. 12: 19-28. FALKAI, P., BOGERTS, B., SCHNEIDER, T., GREVE, B., PFEIFFER, U., PILZ, K., GONSIORZCYK, C., MAJTENYI, C. and OVARY, I. (1995) Disturbed planum temporale asymmetry in schizophrenia. A quantitative post-mortem study. Schizophr. Res. 14:161-176. FRANGOU, S., SHARMA, T., SIGMUDSSON, T., BARTA, P., PEARLSON, G. and MURRAY, R.M. (1997) The Maudsley Family Study, 4: Normal planum temporale asymmetry in familial schizophrenia. A volumetric MRI study. Br. J. Psychiat. 170: 328-333.
Neurochemical asymmetry in schizophrenic temporal lobe
875
GESCHWIND, N. and GALABUEDA, A.M. (1985) Cerebral lateralization, biological mechanism, associations, and pathology: I. A hypothesis and a program for research. Archives of Neurol. 42: 428-459. GUREVICH, E.V. and JOYCE, J.N. (1997) Alterations in the cortical serotonergic system in schizophrenia: A postmortem study. Biol. Psychiat. 42:529-545. HASHIMOTO, T., KITAMURA, K., KAJIMOTO, Y., SHIRAI, Y., SHIRAKAWA, O., MITA, T., NISHINO, N. and TANAKA, C. (1993) Differential changes in serotonin 5-HT 1A and 5-HT2 receptor binding in patients with chronic schizophrenia. Psychopharmacol. 112: $35-$39. HIGHLEY, J.R., MCDONALD, B.B., WALKER, M.A., ESIRI, M.M. and CROW, T.J. (2000) Schizophrenia and temporal lobe asymmetry A post-mortem stereological study of tissue volume. Br. J. Psychiat.175: 127-134. HIRAYASU, Y., SHENTON, M.E., SALISBURY, D.F., DICKEY, C.C., FISCHER, I.A., MAZZONI, P., KISLER, T., ARAKAKI, H., Kwon, J.S., ANDERSON, J.E., YURGELUN-Todd, D., TOHEN, M. and MCCARLEY, R.W. (1998) Lower left temporal lobe MRI volumes in patients with first-episode schizophrenia compared with psychotic patients with first-episode affective disorder and normal subjects. Am. J. Psychiat. 155:1384-1391. HOFF, A.L., RIORDAN, H., O'DONNELL, D., STRITZKE, P., NEALE, C., BOCCIO, A., ANAND, A.K. and DELISI, L.E. (1992) Anomalous lateral sulcus asymmetry and cognitive function in first-episode schizophrenia. Schizophr. Bull. 18:257-272. KERWIN, R.W., PATEL, S., MELDRUM, B.S., CZUDEK, C. and REYNOLDS, G.P. (1988)Asymmetrical loss of glutamate receptor subtype in left hippocampus in schizophrenia. Lancet I (8585): 583-584. KESHAVAN, M.S., HAAS, G.L., KAHN, C.E., AGUILAR, E., DICK, E.L., SCHOOLER, N.R., SWEENEY, J.A. and PE'Iq'EGREW, J.W. (1998) Superior temporal gyms and the course of early schizophrenia: progressive, static, or reversible? J. Psychiatr. Res. 32:161-167. KITAMURA, N., NISHINO, N., HASHIMOTO, T., KAJIMOTO, Y., SHIRAI, Y., MURAKAMI, N., YANG, C.-Q., LIN, X.-H., YAMAMOTO, H., NAKAI, T., MITA, T., KOMURE, O., SHIRAKAWA, O. and NAKAI, H. (1998) Asymmetrical changes in the fodrin _ subunit in the superior temporal cortices in schizophrenia. Biol. Psychiat. 43: 254-262. KWON, J.S., MCCARLEY, R.W., HIRAYASU, Y., ANDERSON, J.E., FISCHER, I.A., KIKINIS, R., JOLESZ, F.A. and SHENTON, M.E. (1999) Left planum temporale volume reduction in schizophrenia. Arch. Gen. Psychiat. 56:142-148. LIN, X.-H., KITAMURA, N., HASHIMOTO, T., SHIRAKAWA, O. and MAEDA, K. (1988) Opposite Changes in Phosphoinositide-specific Phospholipase C in the Left Prefrontal and Superior Temporal Cortex of Patients with Chronic Schizophrenia. Biol. Psychiatry. 46:1665-1671.
876
O. S h i r a k a w a et aL
MITA, T., HANADA, S., NISHINO, N., KUNO, T., NAKAI, H., YAMADORI, T., MIZOI, Y. and TANAKA, C. (1986) Decreased serotonin $2 and increased dopamine D2 receptors in chronic schizophrenics. Biol Psychiat. 21:1407-1414. NISHINO, O., KITAMURA, N., HASHIMOTO, T., KAJIMOTO, Y., SHIRAI, Y., MURAKAMI, N., NAKAI, T., KOMURE, O., SHIRAKAWA, O., MITA, T. and NAKAI, H. (1993) Increase in [3H]cAMP binding sites and decrease Gict and Goa immunoreactivities in left temporal cortices from patients with schizophrenia. Brain Res. 615: 41-49. PEARLSON, G.D., BARTA, P.E., POWERS, R.E., MENON, R.R., RICHARDS, S.S., AYLWARD, E.H., FEDERMAN, E.B., CHASE, G,A., PETTY, R.G. and TIEN, A.Y. (1988)Ziskind-Somerfeld Research Award 1996. Medial and superior temporal gyral volumes and cerebral asymmetry in schizophrenia versus bipolar disorder. Biol. Psychiat. 41:1-14. PETTY, R.G., BARTA, P.E., PEARL,SON, G.D., MCGILCHIRIST, I.K., LEWIS, R.W., TIEN, A.Y., PULVER, A., DARRELL VAUGHN, D., CASANOVA, M.F. and POWERS, R.E. (1995) Reversal of asymmetry of the planum temporale in schizophrenia. Am. J. Psychiat. 152:715-721. PETTY, R.G. (1999) Structural asymmetries of the human brain and their disturbance in schizophrenia. Schizophr. Bull. 2: 121-139. REYNOLDS, G.P. (1983) Increased concentrations and lateral asymmetry of amygdala dopamine in schizophrenia. Nature 305(5935k527-529. REYNOLDS, G.P., CZUDEK, C. and ANDREWS, H.B. (1990) Deficit and hemispheric asymmetry of GABA uptake sites in the hippoeampus in schizophrenia. Biol. Psychiat. 27:1038-44. ROSSI, A., STRATTA, P., MATTEI, P., CUPILLARI, M., BOZZAO, A., GALLUCCI, M. and CASACCHIA, M. (1992) Planum temporale in schizophrenia: A magnetic resonance study. Schizophr. Res. 7:19-22. ROTH, B.L., BERRY, S.A., KROEZE, W.K., WILLINS, D.L. and KRISTIANSEN, K. (1988)Serotonin 5-HT2A receptors: Molecular Biology and Mechanisms of Regulation. Crit. Rev. in Neurobiol. 12 : 319-338. SHAPLESKE, J., ROSSELL, S.L., WOODRUFF, P.W.R. and DAVID, A.S. (1999) The planum temporale: a systematic,quantitative review of its structural, functional and clinical significance. Brain Res. Rev. 29: 26-49. SHENTON, M.E.; KIKININS, R., JOLESZ, F.A., POLLACK, S.D., LEMAY, M., WIBLE, C.G., HOKAMA, H., MERTIN, J., METCALF, D., COLEMAN, M. and MCCARLEY, R.W. (1992) Abnormalities of the left temporal lobe and thought disorder in schizophrenia: A quantitative magnetic resonance imaging study. New Eng. J. Med. 327:604-612. YANG, C.-Q., KITAMURA, N., NISHINO, N., SHIRAKAWA, O. and NAKAI, H. (1988) Isotype-specific G protein abnormalities in the left superior temporal cortex
Neurochemical asymmetry in schizophrenic temporal lobe
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and limbic structures of patients with chronic schizophrenia. Biol. Psychiat. 43: 12-19.
Inquiries and reprint requests should be addressed to:
Osamu Shirakawa, M.D., Ph.D., Department of Psychiatry and Neurology, Kobe University School of Medicine, 7-5-1 Kusunoki-cho Chuo-Ku Kobe 650-0017, Japan TEL: +81-78-382-6065 FAX: +81-78-382-6079