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A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives

  • Francine M Benes
    Correspondence
    Address reprint requests to Francine M. Benes, MD, PhD, McLean Hospital, 115 Mill Street, Belmont, MA 02178
    Affiliations
    Laboratory for Structural Neuroscience, McLean Hospital, Belmont, Massachusetts, USA (FMB, EWK, SLV, MST)

    Program of Neuroscience (FMB) and Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA (FMB, SLV)
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  • Esther W Kwok
    Affiliations
    Laboratory for Structural Neuroscience, McLean Hospital, Belmont, Massachusetts, USA (FMB, EWK, SLV, MST)

    Program of Neuroscience (FMB) and Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA (FMB, SLV)
    Search for articles by this author
  • Stephen L Vincent
    Affiliations
    Laboratory for Structural Neuroscience, McLean Hospital, Belmont, Massachusetts, USA (FMB, EWK, SLV, MST)

    Program of Neuroscience (FMB) and Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA (FMB, SLV)
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  • Mark S Todtenkopf
    Affiliations
    Laboratory for Structural Neuroscience, McLean Hospital, Belmont, Massachusetts, USA (FMB, EWK, SLV, MST)

    Program of Neuroscience (FMB) and Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA (FMB, SLV)
    Search for articles by this author

      Abstract

      Background: Recent studies have suggested that there may be a preferential decrease of “nonpyramidal” neurons (NPs) in several corticolimbic regions of schizophrenic (SZ) brain. The current study was undertaken to determine whether a change in the density of pyramidal neurons (PNs) and NPs might be present in the hippocampal formation (HIPP) of SZ brain.
      Methods: A spatial counting approach in which the location of each and every PN and NP in the stratum pyramidale of sectors CA1–4 was applied to 11 normal control (CONs) and 10 SZs matched for age and postmortem interval, as well as 4 manic depressive (MD) subjects matched for age.
      Results: The data indicate that the CONs had approximately 10–20 times as many PNs than NPs in the various HIPP subfields. When the CON data were compared to those for the SZs, both the total number and density of PNs were found to be similar in all four sectors, while NPs were found to be selectively reduced by approximately 40% in CA2 of the SZ group. When the data were broken down according to patients with and without neuroleptic exposure, drug-free SZs showed a significant reduction in the density of NPs in CA2. The 4 MD cases both with and without neuroleptic exposure also showed a similar reduction of NPs in sector CA2.
      Conclusions: Taken together, the results of this study suggest that there may be a highly selective decrease in the number of NPs in sector CA2 that could play a contributory role in the pathophysiology of the major psychoses.

      Keywords

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      References

        • Abercrombie M
        Estimation of nuclear population from microtomic sections.
        Anat Rev. 1946; 94: 239
        • Akbarian S
        • Kim J.J
        • Potkin S.G
        • Hagman J.O
        • Tafazzoli A
        • Bunney W.E
        • et al.
        Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics.
        Arch Gen Psychiatry. 1995; 52: 258-278
        • Arnold S.E
        • Franz B.R
        • Gur R.C
        • Gur R.E
        • Shapiro R.M
        • Moberg P.J
        • et al.
        Smaller neuron size in schizophrenia in hippocampal subfields that mediate cortical-hippocampal interactions.
        Am J Psychiatry. 1995; 152: 738-748
        • Benes F.M
        A neurodevelopmental approach to the understanding of schizophrenia and other mental disorders.
        in: Cicchetti D Cohen D.J Developmental Psychopathology, vol 1 Theory and Methods. Wiley, New York1995: 227-253
        • Benes F.M
        The role of stress and dopamine-GABA interactions in the vulnerability for schizophrenia.
        J Psychiatr Res. 1997; 31: 257-275
        • Benes F.M
        • Davidson J
        • Bird E.D
        Quantitative cytoarchitectural studies of cerebral cortex of schizophrenics.
        Arch Gen Psychiatry. 1986; 43: 31-35
        • Benes F.M
        • McSparren J
        • Bird E.D
        • Vincent S.L
        • SanGiovanni J.P
        Deficits in small interneurons in prefrontal and anterior cingulate cortex of schizophrenic and schizoaffective patients.
        Arch Gen Psychiatry. 1991; 48: 996-1001
        • Benes F.M
        • Sorensen I
        • Bird E.D
        Morphometric analyses of the hippocampal formation in schizophrenic brain.
        Schizophr Bull. 1991; 17: 597-608
        • Benes F.M
        • Vincent S.L
        • Alsterberg G
        • Bird E.D
        • SanGiovanni J.P
        Increased GABA-A receptor binding in superficial layers of cingulate cortex in schizophrenics.
        J Neurosci. 1992; 12: 924-929
        • Benes F.M
        • Khan Y
        • Vincent S.L
        • Wickramasinghe R
        Differences in subregional and cellular distribution of GABAA receptor binding in the hippocampal formation of schizophrenic brain.
        Synapse. 1996; 22: 338-349
        • Benes F.M
        • Vincent S.L
        • Marie A
        • Khan Y
        Upregulation of GABAA receptor binding on neurons of prefrontal cortex in schizophrenic subjects.
        Neuroscience. 1996; 75: 1021-1031
        • Benes F.M
        • Wickramasinghe R
        • Vincent S.L
        • Khan Y
        • Todtenkopf M.S
        Uncoupling of GABAA and benzodiazepine receptor binding activity in the hippocampal formation of schizophrenic brain.
        Brain Res. 1997; 755: 121-129
        • Bentoviglio M
        • Kultas-Ilinsky K
        • Ilinsky I
        Limbic thalamus.
        in: Vogt B.A Gabriel M Neurobiology of Cingulate Cortex and Limbic Thalamus. Birkhauser, Boston1993: 71-122
        • Bogerts B
        • Meertz E
        • Schonfeldt-Bausch R
        Basal ganglia and limbic system pathology in schizophrenia.
        Arch Gen Psychiatry. 1985; 42: 784-791
        • Coggeshall R.E
        • Lekan H.A
        Methods for determining numbers of cell and synapses.
        J Comp Neurol. 1996; 364: 6-15
        • Colon E.J
        Quantitative cytoarchitectonics of the human cerebral cortex.
        Psychiatr Neurol Neurochir. 1971; 74: 291-302
        • Dom R
        Neostriatal and Thalamic Interneurons. Their Role in the Pathophysiology of Huntington’s Chorea, Parkinson’s Disease and Catatonic Schizophrenia. Katholieke Universiteit Leuven, Leuven1976
        • Domesick V.B
        Projections from the cingulate cortex in the rat.
        Brain Res. 1969; 12: 296-320
        • Falkai P
        • Bogerts B
        Cell loss in the hippocampus of schizophrenics.
        Eur Arch Psychiatry Neurol Sci. 1986; 236: 154-161
        • Feighner J.P
        • Robins E
        • Guze S.B
        Diagnostic criteria for use in psychiatric research.
        Arch Gen Psychiatry. 1972; 26: 57-63
        • Feldman S
        • Robinson S
        Electrical activity of the brain in adrenalectomized rats with implanted electrodes.
        J Neurol Sci. 1968; 6: 1-8
        • Goldman-Rakic P.S
        • Selemon L.D
        • Schwartz M.L
        Dual pathways connecting the dorsolateral prefrontal cortex with the hippocampal formation and parahippocampal cortex in the rhesus monkey.
        Neuroscience. 1984; 12: 719-743
        • Gundersen H.J.G
        • Bagger P
        • Bendtsen T.F
        • Evans S.M
        • Korbo L
        • Marcussen N
        • et al.
        The new stereological tools.
        Acta Pathol Methodol Immunol Sci. 1988; 96: 857-881
        • Harrison P.J
        • McLaughlin D
        • Kerwin R.W
        Decreased hippocampal expression of a glutamate receptor gene in schizophrenia.
        Lancet. 1991; 337: 450-452
        • Heckers S
        • Heinsen H
        • Geiger B
        • Beckmann H
        Hippocampal neuron number in schizophrenia.
        Arch Gen Psychiatry. 1991; 48: 1002-1008
        • Irle E
        • Markowitsch H.J
        Widespread cortical projection of the hippocampal formation in the cat.
        Neuroscience. 1982; 7: 2637-2647
        • Jakob H
        • Beckmann H
        Prenatal developmental disturbances in the limbic allocortex in schizophrenics.
        J Neural Transm. 1986; 65: 303-326
        • Jeste D
        • Lohr J.B
        Hippocampal pathologic findings in schizophrenia.
        Arch Gen Psychiatry. 1989; 46: 1019-1024
        • Kerwin R.W
        • Patel S
        • Meldrum B.S
        • Czudek C
        • Reynolds G.P
        Asymmetrical loss of glutamate receptor subtype in left hippocampus in schizophrenia.
        Lancet. 1988; i: 583-584
        • Kerwin R
        • Patel S
        • Meldrum B
        Quantitative autoradiographic analysis of glutamate binding sites in the hippocampal formation in normal and schizophrenic brain post mortem.
        Neuroscience. 1990; 39: 25-32
        • Kovelman J.A
        • Scheibel A.B
        A neurohistological correlate of schizophrenia.
        Biol Psychiatry. 1984; 19: 1601-1621
        • Lambert J.J
        • Peters J.A
        • Cottrell G.A
        Actions of synthetic and endogenous steroids on the GABAA receptor.
        Trends Pharmacol Sci. 1987; 8: 224-227
        • Majewska M.D
        • Bisserbe J.-C
        • Eskay L.R
        Glucocorticoids are modulators of GABAA receptors in brain.
        Brain Res. 1985; 339: 178-182
        • McEwen B.S
        Glucocorticoids and hippocampus.
        in: Ganten D Pfaff D Adrenal Actions on Brain. Springer-Verlag, Berlin1982: 1-22
        • Miller A.L
        • Chaptal C
        • McEwen B.S
        • Beck J.R.E
        Modulation of high affinity GABA uptake into hippocampal synaptosomes by glucocorticoids.
        Psychoneuroendocrinology. 1978; 3: 155-164
        • Monaghan D.T
        • Cotman C.W
        Distribution of N-methyl-D-aspartate-sensitive L-3H-glutamate-binding sites in rat brain.
        J Neurosci. 1985; 5: 2905-2919
        • Pakkenberg B
        Pronounced reduction of total neuron number in mediodorsal thalamic nucleus and nucleus accumbens in schizophrenic brain.
        Arch Gen Psychiatry. 1990; 47: 1023-1028
        • Pakkenberg B
        Total nerve cell number in neocortex in chronic schizophrenics and controls estimated using optical dissectors.
        Biol Psychiatry. 1993; 34: 768-772
        • Pandya D.N
        • Van Hoesen G.W
        • Mesulam M.-M
        Efferent connections of the cingulate gyrus in the rhesus monkey.
        Exp Brain Res. 1981; 42: 319-330
        • Pfaff D.W
        • Silva M.T.A
        • Weiss J.M
        Telemetered recording of hormone effects on hippocampal neurons.
        Science. 1971; 172: 394-395
        • Reynolds G.P
        • Czudek C
        • Andrews H
        Deficit and hemispheric asymmetry of GABA uptake sites in the hippocampus in schizophrenia.
        Biol Psychiatry. 1990; 27: 1038-1044
        • Rosene D.L
        • Van Hoesen G.W
        The hippocampal formation of the primate brain.
        in: Peters A Jones E.G Cerebral Cortex, vol 6 Further Aspects of Cortical Function, Including Hippocampus. Plenum Press, New York1987: 345-456
        • Saper C.B
        Any way you cut it.
        J Comp Neurol. 1996; 364: 5
        • Sapolsky R.M
        Stress, the Aging Brain, and the Mechanisms of Neuron Death. MIT Press, Cambridge, MA1992
        • Schwarcz R
        • Coyle J.T
        Neurochemical sequelae of kainate injections in corpus striatum and substantia nigra of the rat.
        Life Sci. 1977; 20: 431-436
        • Selemon L.D
        • Rajkowska G
        • Goldman-Rakic P.S
        Abnormally high neuronal density in the schizophrenic cortex.
        Arch Gen Psychiatry. 1995; 52: 805-818
        • Stumpf W.E
        • Heiss C
        • Sar M
        • Duncan G.E
        • Craver C
        Dexamethasone and corticosterone receptor sites.
        Histochemistry. 1989; 92: 201-210
        • Sutanto W
        • Handelmann G
        • de Bree F
        • de Kloet E.R
        Multifaceted interaction of corticosteroids with the intracellular receptors and with membrane GABAA receptor complex in the rat brain.
        J Neuroendocrinol. 1989; 1: 243-247
      1. Todtenkopf MS, Benes FM (in press): Distribution of glutamate decarboxylase65 immunoreactive puncta on pyramidal and nonpyramidal neurons in hippocampus of schizophrenic brain. Synapse.

        • Vogt B.A
        • Miller M
        Cortical connections between rat cingulate cortex and visual, motor and post-subicular cortices.
        J Comp Neurol. 1983; 216: 192-210
        • Vogt B.A
        • Sikes R.W
        • Vogt L.J
        Anterior cingulate cortex and the medial pain system.
        in: Vogt B.A Gabriel M Neurobiology of Cingulate Cortex and Limbic Thalamus. Birkhäuser, Boston1993: 313-344
        • Weibel E.R
        Stereological Methods, vol 1. Practical Methods for Biological Morphometry. Academic Press, New York1979
        • Williams R.W
        • Rakic P
        Three-dimensional counting.
        J Comp Neurol. 1988; 278: 344-352
        • Woodbury D.M
        Effects of adrenocortical steroids.
        J Pharmacol Exp Ther. 1952; 153: 337-343
        • Zhang W.Q
        • Rogers B.C
        • Tandon P
        • Hudson P.M
        • Sobotka T.J
        • Hong J.S
        • et al.
        Systemic administration of kainic acid increases GABA levels in perfusate from the hippocampus of rats in vivo.
        Neurotoxicology. 1990; 11: 593-600