Original ArticlesA reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives
Introduction
Many postmortem studies of schizophrenic (SZ) brain have focused on the hippocampal formation (HIPP) because of its strategic location within the corticolimbic system and the likelihood that it may contribute to the cognitive disturbances seen in this disorder (Benes 1995). Consistent with this idea, several histopathologic studies have reported shrinkage (Bogerts et al 1985) and neuronal cell loss Falkai and Bogerts 1986, Jeste and Lohr 1989 in this region of SZs, changes that are believed to be related to either a degenerative process Kovelman and Scheibel 1984, Jakob and Beckmann 1986 or a neurodevelopmental distrubance (Benes 1995). Although some studies have not found evidence for a loss of neurons Benes et al 1991b, Heckers et al 1991, Arnold et al 1995, more subtle disturbances at the biochemical and molecular levels appear to be present in this region. For example, a reduction of gamma-aminobutyric acid (GABA) reuptake (Reynolds et al 1990) and an up-regulation of GABAA receptors, particularly in the stratum oriens of sectors CA3 and CA2 (Benes et al 1996a), have been observed in SZs. Unlike this latter receptor, the benzodiazepine receptor is not increased in the hippocampus of SZs, and it is now believed that there may be an uncoupling in the regulation of these two binding sites on the GABAA–chloride ionophore complex (Benes et al 1997).
In a recent study of the distribution of immunoreactivity for the 65-kD isoform of glutamate decarboxylase (GAD65-IR), a neuroleptic dose-related increase of GABAergic terminals was found in the stratum oriens of sectors CA3 and CA2 (Todtenkopf and Benes in press). Interestingly, 2 neuroleptic-free subjects showed the lowest density of GAD65-IR terminals. Thus, the changes in GABAergic terminals observed in SZs in this latter study parallel those observed for the GABAA receptor that were also most marked in stratum oriens of sectors CA3 and CA2. It is not clear, however, whether a decrease of inhibitory inputs to these two subfields may be associated with a selective abnormality affecting the synthesis, storage, or release of this transmitter by axon terminations or, alternatively, with an overt loss of GABAergic cell somata. Interestingly, two studies to date have reported a decrease in the density of interneurons in the anterior cingulate (ACCx) and prefrontal (PFCx) cortices (Benes et al 1991a), as well as the dorsomedial nucleus of the thalamus (Dom 1976). In the case of ACCx (Benes et al 1992) and PFCx (Benes et al 1996b) both regions also show an up-regulation of the GABAA receptor that is thought to represent a compensation for a decrease of GABA cell number and/or activity.
An important strategy that can help distinguish whether an overt loss of GABA cells may occur in the HIPP of SZ brain is to analyze the relative distribution of pyramidal neurons (PNs) and nonpyramidal neurons (NPs) in this region. In the current report, a detailed stereological analysis of PNs and NPs has been conducted in the stratum pyramidale of sectors CA1–4 in the HIPP from a cohort of normal control (CON), SZ, and manic depressive (MD) subjects. Since the relative number of NPs in this region was found to be extremely low (see below), the cell counting technique employed in the present study was a two-dimensional one in which the X-Y coordinates of each and every PN and NP were accurately recorded and related both numerically and spatially to every other neuron in the same plane. Although three-dimensional cell counting is recommended for studies of this type Gundersen et al 1988, Williams and Rakic 1988, Coggeshall and Lekan 1996, Saper 1996, this approach would not have the sensitivity needed to detect a subtle, but significant, change in the number of such a sparsely distributed neuronal subtype.
Section snippets
Subjects
The cases included in this study were obtained from the Harvard Brain Tissue Resource Center located at McLean Hospital and consisted of 11 CONs and 10 SZs (Table 1). A written consent for brain removal was given by the legal next-of-kin for each case. The diagnosis of SZ was made by retrospective review of medical records and family questionnaires using the criteria of Feighner et al (1972). Four MD cases were also included to assess the specificity of findings in the SZs. The Diagnostic and
Results
The distribution of neurons throughout the stratum pyramidale (Figure 1) was represented as a two-dimensional scatterplot for PNs (upper panel) and NPs (lower panel) throughout sectors CA1–4 of a representative CON (left) and SZ (right) case (Figure 2). The total number of PNs (approximately 2000 per case) is much greater than that for NPs (approximately 100–200 per case). As Table 3shows, the ratio between PNs and NPs in each sector ranged from 9:1 in CA2 to 20:1 in sector CA3 of the CON
Discussion
The results of this study indicate that a reduction in the number and density of NPs in sector CA2 may occur in HIPP of SZ brain. As such, these findings are consistent with other postmortem studies in which an up-regulation of GABAA receptor binding activity Benes et al 1996a, Benes et al 1997 and a neuroleptic dose-related increase of GAD65-IR terminals (Todtenkopf and Benes in press) were found to be most strikingly present in sectors CA3 and CA2 of SZs. Taken together, these data provide
Acknowledgements
This work was supported by grants from the National Institute of Mental Health (MH00423, MH42261, MH31154, MH31862) and the Stanley Foundation.
The authors wish to thank Ms. Patti Fitzpatrick and Ms. Maureen Medeiros for their help in preparing this manuscript.
References (55)
The role of stress and dopamine-GABA interactions in the vulnerability for schizophrenia
J Psychiatr Res
(1997)- et al.
Upregulation of GABAA receptor binding on neurons of prefrontal cortex in schizophrenic subjects
Neuroscience
(1996) - et al.
Uncoupling of GABAA and benzodiazepine receptor binding activity in the hippocampal formation of schizophrenic brain
Brain Res
(1997) Projections from the cingulate cortex in the rat
Brain Res
(1969)- et al.
Electrical activity of the brain in adrenalectomized rats with implanted electrodes
J Neurol Sci
(1968) - et al.
Dual pathways connecting the dorsolateral prefrontal cortex with the hippocampal formation and parahippocampal cortex in the rhesus monkey
Neuroscience
(1984) - et al.
Decreased hippocampal expression of a glutamate receptor gene in schizophrenia
Lancet
(1991) - et al.
Widespread cortical projection of the hippocampal formation in the cat
Neuroscience
(1982) - et al.
Asymmetrical loss of glutamate receptor subtype in left hippocampus in schizophrenia
Lancet
(1988) - et al.
Quantitative autoradiographic analysis of glutamate binding sites in the hippocampal formation in normal and schizophrenic brain post mortem
Neuroscience
(1990)