Abstract
Findings. Specific [3H]flunitrazepam binding to “neuronal”-type sites was significantly lower in anterior cingulate cortex, hippocampus, somatomotor cortex, cerebellar cortex, and globus pallidus in small postmortem samples of schizophrenic brains than in non-schizophrenic controls. Four of these five brain regions were reported by others to exhibit atrophy and/or neuronal loss in schizophrenia.Interpretation: Selective loss of hippocampal pyramidal neurons in postmortem schizophrenic brains has been reported (11). Pyramidal neurons are known to be glutamatergic (14, 26) and to exhibit high densities of benzodiazepine binding sites (25,31). Glutamatergic neurons are known to be abundant in most layers of the cerebral cortex, and most of these are pyramidal neurons (26). All layers of the cerebral cortex display high densities of benzodiazepine binding sites (24,25,31). The number of large pyramidal cells is little affected in most layers of the anterior cingulate cortex, but the number of small neurons is significantly lower, particularly in layer II (10). Pyramidal neurons range in size from very large to very small, and many very small pyramidal cells are often counted, together with small “stellate” neurons, as “granule” cells (28). Further, non-pyramidal glutamatergic neurons are reportedly also found in cerebral cortex (26). Thus, it seems possible that the large reduction in [3H]flunitrazepam binding we find in anterior cingulate cortex reflects the selective loss of glutamatergic neurons. The hypothesis that selective loss of glutamatergic neurons form various brain regions is associated with major psychoses can be easily tested by immunohistochemical studies of these regions using glutamate- and GABA-specific antibodies.
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References
Brown, R., Colter, N., Corsellis, J. A. N., Crow, T. J., Frith, C. D., Jagoe, R., Johnstone, E. C., and Marsh, L., 1986. Postmortem evidence of structural brain changes in schizophrenia. Arch. Gen. Psychiat. 43:36–42.
Jest, D. V., Lohr, J. B., and Goodwin, F. K. 1988. Neuroanatomical studies of major affective dissorders. Brit. J. Psychiat. 153:444–459.
Kelsoe, J. R., Jr., L. Cadet, J., Pickar, D., and Weinberger, D. R. 1988. Quantitative neuroanatomy in schizophrenia. Arch. Gen. Psychiat. 45:533–541.
Suddath, R. L., Christison, G. W., Torrey, E. F., Casanova, M. F., and Weinberger, D. R. 1990. Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. N. Engl. J. Med. 322:789–794.
Roberts, G. W. 1991. Schizophrenia: A neuropathological perspective. Brit. J. Psychiat. 158:8–17.
Zipursky, R. B., Lim, K. O., Sullivan, E. V., Brown, B. W., and Pfefferbaum, A. 1992. Widespread cerebral gray matter volume deficits in schizophrenia. Arch. Gen Psychiat. 49:195–205.
Benes, F. M., Davidson, J., and Bird, E. D. 1986. Quantitative cytoarchitectural studies of the cerebral cortex of schizophrenics. Arch. Gen. Psychiat. 43:31–35.
Pakkenberg, B. 1990. Pronounced reduction of total neuron number in mediodorsal thalamic nucleus and nucleus accumbens in schizophrenics. Arch. Gen. Psychiat. 47:1023–1028.
Torrey, E. F. 1991. A viral-anatomical explanation of schizophrenia. Schizophrenia Bull. 17:15–18.
Benes, F. M., McSparren, J., Bird, E. D., SanGiovanni, J. P., and Vincent, S. L. 1991. Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenics and schizoaffective patients. Arch. Gen. Psychiat. 48:996–1001.
Benes, F. M., Sorensen, I., and Bird, E. D. 1991. Reduced neuronal size in posterior hippocampus of schizophrenic patients. Schizophrenia Bull. 17:597–608.
King, D. J., and Cooper, S. J. 1989. Viruses, immunity and mental disorder. Brit. J. Psychiat. 154:1–7.
Ottersen, O. P., and Storm-Mathisen, J. 1985. Different neuronal localization of aspartate-like and glutamate-like immunoreactivitics in the hippocampus of rat, guinea-pig and senegalese baboon (Papio Papio), with a note on the distribution of γ-aminobutyrate. Neuroscience 16:589–606.
Kowall, N. W., and Beal, M. F. 1991. Glutamate-, glutaminase-, and taurine-immunoreactive neurons develop neurofibrillary tangles in Alzheimer's disease. Ann. Neurol. 29:162–167.
Squires, R. F., and Saederup, E. 1991. A review of evidence for GABAergic predominance/glutamatergic deficit as a common etiological factor in both schizophrenia and affective psychoses: more support for a continuum hypothesis of “functional” psychosis. Neurochem. Res. 16:1099–1111.
Young, A. B., Oster-Granite, M. L., Herndon R. M., and Snyder, S. H. 1974. Glutamic acid: selective depletion by viral induced granule cell loss in hamster cerebellum. Brain Res. 73:1–13.
Herndon, R. M., Margolis, G., and Kilham L. 1971. The synaptic organization of the malformed cerebellum induced by perinatal infection with the feline panleukopenia virus (PLV). J. neuropathol. Exp. Neurol. 30:196–205.
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition, revised. Washington, D.C., American Psychiatric Association 1987.
Palkovits, M. 1973. Isolated removal of hypothalamic or other brain nuclei of the rat. Brain Res. 59:449–450.
Squires, R. F., and Saederup, E. 1982. γ-Aminobutyric acid receptors modualte cation binding sites coupled to independent benzodiazepine, picrotoxin, and anion binding sites. Mol. Pharmacol. 22:327–334.
Squires R. F., and Saederup, E. 1989. Polychlorinated convulsant insecticides potentiate the protective effect of NaCl against heat inactivation of [3H]flunitrazepam binding sites. J. Neurochem. 52:537–543.
Braestrup, C., and Squires, R. F. 1977. Specific benzodiazepine receptors in rat brain characterized by high-affinity [3H]diazepam binding. Proc. Natl. Acad. Sci. USA 74:3805–3809.
Braestrup, C., Albrechtsen, R., and Squires, R. F. 1977. High densities of benzodiazepine receptors in human cortical areas. Nature 269:702–704.
Young, W. S. III, and Kuhar, M. J. 1979. Radiohistochemical localization of benzodizepine receptors in rat brain. J. Pharmacol. Exp. Ther. 212:337–346.
Richards, J. G., Schoch, P., Haring, P., Takacs, B., and Mohler, H. 1987. Resolving GABAA/benzodiazepine receptors: cellular and subcellular localization in the CNS with monoclonal antibodies. J. Neurosci. 7:1866–1886.
Conti, F., Rustioni, A., Petrusz, P., and Towle, A. C. 1987. Glutamate-positive neurons in the somatic sensory cortex of rats and monkeys. J. Neursci. 7:1887–1901.
Ottersen, O. P., and Storm-Mathisen, J. 1984. Glutmate-and GABA-containing neurons in the mouse and rat brain, as demonstrated with a new immunocytochemical technique. J. Comp. Neurol. 229:374–392.
Braak, H. 1984. Architectonics as seen by lipofuscin stains. Pages 59–99,in Peters, A., Jones, E. G. (eds.) Cerebral Cortex Vol I, Plenum Press, New York.
Pritchett, D. B., Sontheimer, H., Shivers, B. D., Ymer, S., Kettenmann, H., Schofield, P. R., and Seeburg, P. H. 1989. Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology, Nature 338:582–585.
Sequier, J. M., Richards, J. G., Malherbe, P., Price, G. W., Mathews, S., and Mohler, H. 1988. Mapping of brain areas containing RNA homologous to cDNAs encoding the α and β subunits of the rat GABAA γ-aminobutyrate receptor. Proc. Natl. Acad. Sci. 85:7815–7819.
Wisden, W., Laurie, D. J., Monyer, H., and Seeburg, P. H. 1992. The distribution of 13 GABAA receptor subunits mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon. J. Neurosci. 12:1040–1062.
Herb, A., Wisden, W., Luddens, H., Puia, G., Vicini, S., and Seeburg, P. H. 1992. The third subunit of the γ-aminobutyric acid type A receptor family. Proc. Natl. Acad. Sci. 89:1433–1437.
Benes, F. M., Vicent, S. L., Alsterberg, G., Bird, E. D., and SanGiovanni, J. P. 1992. Increased GABAA receptor binding in superficial layers of cingulate cortex in schizophrenics. J. Neurosci. 12:924–929.
Benes, F. M., Majocha R., Bird, E. D., and Marotta, C. A. 1987. Increased vertical axon numbers in cingulate cortex of schizophrenics. Arch. Gen. Psychiat. 44:1017–1021.
Hanada, S., Mita, T., Nishino, N., and Tanaka, C. 1987. [3H]Muscimol binding sites increased in autopsied brains of chronic schizophrenics. Life Sci. 40:259–266.
Cross, A. J., Crow, T. J., and Owens, F. 1979. Gamma-aminobutyric acid in the brain schizophrenia. Lancet, March 10, 1979, pp. 560–561.
Wamsley, J. K., McCabe, R. T. and Gehlert, D. R. 1986. Autoradiographic localization of binding sites in several GABA and benzodiazepine receptor complexes. Pages 79–89, in Squires, R. F. (ed.), GABA and Benzodiazepine Receptors Vol I, CRC Press, Florida.
Bogerts, B., Meertz, E., and Schonfeldt-Bausch, R. 1985. Basal ganglia and limbic system pathology in schizophrenia. Arch. Gen. Psychiat. 42:784–791.
Stevens, J. R. 1988. Epilepsy, psychosis and schizophrenia. Schizophrenia Res. 1:79–89.
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Squires, R.F., Lajtha, A., Saederup, E. et al. Reduced [3H]flunitrazepam binding in cingulate cortex and hippocampus of postmortem schizophrenic brains: Is selective loss of glutamatergic neurons associated with major psychoses?. Neurochem Res 18, 219–223 (1993). https://doi.org/10.1007/BF01474687
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DOI: https://doi.org/10.1007/BF01474687