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Emerging principles of altered neural circuitry in schizophrenia
Abstract
This paper presents an overview of recent microscopic studies that have sought to define how limbic circuitry may be altered in postmortem schizophrenic brain. The discussion is organized around several basic questions regarding the manner in which interconnections within and between the anterior cingulate cortex and hippocampal formation and involving the glutamate, GABA and dopamine systems may contribute to the pathophysiology of this disorder. The answers to these questions are used to derive several conclusions regarding circuitry changes in schizophrenia: 1) Schizophrenia is not a 'typical' degenerative disorder, but rather it is one in which excitotoxicity may contribute to neuronal pathology, whether or not cell death occurs; 2) Three or more neurotransmitter systems may be simultaneously altered within a single microcircuit; 3) Each transmitter system may show circuitry changes in more than one region, but such changes may vary on a region-by-region basis; 4) The pathophysiology of schizophrenia may involve 'mis-wirings' in intrinsic circuits (microcircuitry) within a given region, but significant changes are probably also present at the level of interconnections between two or more regions within a network (macrocircuitry); 5) While some microscopic findings appear to be selectively present in schizophrenia and be related to a susceptibility gene for this disorder, others may also be present in patients with bipolar disorder; 6) Although some of the circuitry changes seen in schizophrenia and bipolar disorder seem to be associated with neuroleptic exposure, most are not and may reflect the influence of non-specific environmental factors such as pre- and/or postnatal stress; 7) Normal postnatal changes at the level of both macro- and microcircuitry within the limbic system may serve as 'triggers' for the onset of schizophrenia during adolescence. Taken together, these emerging principles can provide a framework for future postmortem studies of schizophrenic brain.
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“multiple lines of evidence in schizophrenia, from electrophysiological, genetic analyses, brain imaging and studies in postmortem brains have implicated oligodendrocyte and myelin dysfunction in this disease”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Benes, 2000
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Dopamine β-Hydroxylase Activity in Brains of Chronic Schizophrenic Patients
Wyatt, R. J., Schwartz, M. A., Erdelyi, E., & Barchas, J. D. (1975) · Science · doi:10.1126/science.1111112 · Cited by 118
Regional neuropathology in schizophrenia: Where are we? Where are we going?
Shapiro, R. M. (1993) · Schizophrenia Research · doi:10.1016/0920-9964(93)90057-p · Cited by 117
Jacobsen, B., & Kinney, D. K. (1980) · Acta Psychiatrica Scandinavica · doi:10.1111/j.1600-0447.1980.tb07709.x · Cited by 107
The role of stress and dopamine-GABA interactions in the vulnerability for schizophrenia
Benes, F. M. (1997) · Journal of Psychiatric Research · doi:10.1016/s0022-3956(96)00044-1 · Cited by 102
Self-citationHuntley, G. W., Morrison, J. H., Prikhozhan, A., & Sealfon, S. C. (1992) · Molecular Brain Research · doi:10.1016/0169-328x(92)90107-m · Cited by 100
Rétaux, S., Besson, M., & Penit-Soria, J. (1991) · Neuroscience · doi:10.1016/0306-4522(91)90150-m · Cited by 100
Benes, F. M., Vincent, S. L., & Molloy, R. P. (1993) · Synapse · doi:10.1002/syn.890150405 · Cited by 98
Self-citationAdaptation to stress: Tyrosine hydroxylase activity and catecholamine release
Stone, E. A., & McCarty, R. C. (1983) · Neuroscience & Biobehavioral Reviews · doi:10.1016/0149-7634(83)90005-2 · Cited by 86
ANTICONVULSANT ACTIVITY OF STEROIDS: SEPARABILITY OF ANTICONVULSANT FROM HORMONAL EFFECTS
Craig, C. R. (1966) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)27399-2 · Cited by 83
Benes, F. M., Wickramasinghe, R., Vincent, S. L., Khan, Y., & Todtenkopf, M. S. (1997) · Brain Research · doi:10.1016/s0006-8993(97)00113-3 · Cited by 82
Self-citationPre- and perinatal complications and risk for bipolar disorder: a retrospective study
Kinney, D. K., Yurgelun-Todd, D. A., Tohen, M. F., & Tramer, S. J. (1998) · Journal of Affective Disorders · doi:10.1016/s0165-0327(98)00015-9 · Cited by 79
The heterogeneity of schizoaffective disorder: implications for treatment
Levitt, J. J., & Tsuang, M. T. (1988) · American Journal of Psychiatry · doi:10.1176/ajp.145.8.926 · Cited by 79
McDonald, A. J., Beitz, A. J., Larson, A. A., Kuriyama, R., Sellitto, C., & Madl, J. E. (1989) · Neuroscience · doi:10.1016/0306-4522(89)90261-3 · Cited by 78
Multiple Forms of Brain Monoamine Oxidase in Schizophrenic and Normal Individuals
Schwartz, M. A. (1974) · Archives of General Psychiatry · doi:10.1001/archpsyc.1974.01760160097020 · Cited by 74
Squires, R. F., Lajtha, Á., Saederup, E., & Palkovits, M. (1993) · Neurochemical Research · doi:10.1007/bf01474687 · Cited by 70
Noack, H. J., & Lewis, D. A. (1989) · Brain Research · doi:10.1016/0006-8993(89)90327-2 · Cited by 68
GAMMA-AMINOBUTYRIC ACID IN THE BRAIN IN SCHIZOPHRENIA
Cross, A. J., Crow, T. J., & Owen, F. (1979) · The Lancet · doi:10.1016/s0140-6736(79)90991-7 · Cited by 67
Modulation of high affinity GABA uptake into hippocampal synaptosomes by glucocorticoids
Miller, A. L., Chaptal, C., McEwen, B. S., & Peck, E. J. (1978) · Psychoneuroendocrinology · doi:10.1016/0306-4530(78)90003-3 · Cited by 67
Eccles, J. C. (1984) · Cerebral cortex · doi:10.1007/978-1-4615-6610-6_1 · Cited by 66
Catecholaminergic innervation of the hippocampus in the cynomolgus monkey
Samson, Y., Wu, J. J., Friedman, A. H., & Davis, J. N. (1990) · The Journal of Comparative Neurology · doi:10.1002/cne.902980209 · Cited by 64
Vincent, S. L., Adamec, E., Sorensen, I., & Benes, F. M. (1994) · Synapse · doi:10.1002/syn.890170104 · Cited by 59
Self-citationDopamine metabolism increases in post-mortem schizophrenic basal ganglia
Toru, M., Nishikawa, T., Mataga, N., & Takashima, M. (1982) · Journal of Neural Transmission · doi:10.1007/bf01254928 · Cited by 57
Rétaux, S., Besson, M., & Penit-Soria, J. (1991) · Neuroscience · doi:10.1016/0306-4522(91)90296-z · Cited by 56
Good, P. F., Huntley, G. W., Rogers, S. W., Heinemann, S. F., & Morrison, J. H. (1993) · Brain Research · doi:10.1016/0006-8993(93)90102-s · Cited by 50
Brain and adrenal tyrosine hydroxylase activity after chronic footshock stress
Stone, E. A., Freedman, L. S., & Morgano, L. E. (1978) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(78)90057-6 · Cited by 48
Benes, F. M. (1988) · PubMed · Cited by 48
Self-citationIncreased density of entorhinal glutamate-immunoreactive vertical fibers in schizophrenia
Longson, D., Deakin, J. F. W., & Benes, F. M. (1996) · Journal of Neural Transmission · doi:10.1007/bf01276423 · Cited by 43
Self-citationEvidence for axonal loss in regions occupied by senile plaques in Alzheimer cortex
Benes, F. M., Farol, P. A., Majocha, R. E., Marotta, C. A., & Bird, E. D. (1991) · Neuroscience · doi:10.1016/0306-4522(91)90034-l · Cited by 40
Self-citationIuvone, P. M., & Dunn, A. J. (1986) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1986.tb00687.x · Cited by 37
Dexamethasone and corticosterone receptor sites
Stumpf, W. E., Heiss, C., Sar, M., Duncan, G. E., & Craver, C. (1989) · Histochemistry and Cell Biology · doi:10.1007/bf00500919 · Cited by 37
Sutanto, W., Handelmann, G. E., de Bree, F. M., & de Kloet, E. R. (1989) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.1989.tb00111.x · Cited by 34
Programmed cell death — many questions still to be answered
Binder, C. R., & Hiddemann, W. (1994) · Annals of Hematology · doi:10.1007/bf01698481 · Cited by 27
Zhang, W. Q., Rogers, B. C., Tandon, P., Hudson, P. M., Sobotka, T. J., Hong, J., & Tilson, H. A. (1990) · PubMed · Cited by 25
Remitting Schizophrenia as a Variant of Affective Disorder*
Fowler, R. C. (1978) · Schizophrenia Bulletin · doi:10.1093/schbul/4.1.68 · Cited by 25
Vargo, J. M., & Marshall, J. F. (1996) · Synapse · doi:10.1002/(sici)1098-2396(199604)22:4 · Cited by 24
Self-citationNeonatal raphe lesions increase dopamine fibers in prefrontal cortex of adult rats
Taylor, J. B., Cunningham, M. C., & Benes, F. M. (1998) · Neuroreport · doi:10.1097/00001756-199806010-00026 · Cited by 22
Self-citationHigh resolution imaging of receptor binding in analyzing neuropsychiatric diseases.
Benes, F., Vincent, S. L., & Giovanni, J. P. S. (1989) · PubMed · Cited by 21
Self-citationElectrical activity of the brain in adrenalectomized rats with implanted electrodes
Feldman, S., & Robinson, S. (1968) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(68)90121-4 · Cited by 13
Benes, F. M. (1997) · Schizophrenia Bulletin · doi:10.1093/schbul/23.3.503 · Cited by 11
Self-citationIs there evidence for neuronal loss in schizophrenia?
Benes, F. M. (1997) · International Review of Psychiatry · doi:10.1080/09540269775295 · Cited by 10
Self-citationBerlin and global warming policy
Bolin, B., & Houghton, J. T. (1995) · Nature · doi:10.1038/375176a0 · Cited by 5
Xiao (1998) · doi:10.1002/(sici)1098-2396(199808)29:4
Self-citationBenes (1996) · doi:10.1002/(sici)1098-2396(199608)23:4
Self-citation
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Metadata
- Authors
- Benes, F.
- Affiliations
- Harvard University (US)
- Corresponding author
- Benes, F
- ORCID
- Benes, F
- Venue
- Brain Research Reviews
- Publisher
- Elsevier BV
- Published
- 2000-03
- Volume
- 31
- Issue
- 2-3
- Pages
- 251-269
- ISSN
- 0165-0173 (ISSN-L)
- OpenAlex
- W2066213630
- Cited by
- 513
- References
- 161
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 6 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 4 · 2019: 4 · 2018: 7 · 2017: 7 · 2016: 10 · 2015: 20 · 2014: 8 · 2013: 14 · 2012: 15
- FWCI
- 28.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Research Reviews (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (MH-42261, MH00423, MH31152)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- schizophrenia, limbic system, neural circuits, anterior cingulate cortex, hippocampal formation, glutamatergic system, GABA system, dopaminergic system, excitotoxicity, microcircuitry, bipolar disorder, prenatal stress, postnatal development, schizophrenia pathophysiology, postmortem brain
- MeSH terms
- Animals, Humans, Limbic System, Neural Pathways, Schizophrenia
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