S100B-immunopositive glia is elevated in paranoid as compared to residual schizophrenia: A morphometric study

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Abstract

Objective

Several studies have revealed increased S100B levels in peripheral blood and cerebrospinal fluid (CSF) of patients with schizophrenia. In this context, it was postulated that elevated levels of S100B may indicate changes of pathophysiological significance to brain tissue in general and astrocytes in particular. However, no histological study has been published on the cellular distribution of S100B in the brain of individuals with schizophrenia to clarify this hypothesis.

Methods

The cell-density of S100B-immunopositive glia was analyzed in the anterior cingulate, dorsolateral prefrontal (DLPF), orbitofrontal, and superior temporal cortices/adjacent white matter, pyramidal layer/alveus of the hippocampus, and the mediodorsal thalamic nucleus of 18 patients with schizophrenia and 16 matched control subjects.

Results

Cortical brain regions contained more S100B-immunopositive glia in the schizophrenia group relative to controls (P = 0.046). This effect was caused by the paranoid schizophrenia subgroup (P = 0.018). Separate analysis of white matter revealed no diagnostic main group effect (P = 0.846). However, the white matter of patients with paranoid schizophrenia contained more (mainly oligodendrocytic) S100B-positive glia as compared to residual schizophrenia (P = 0.021). These effects were particularly pronounced in the DLPF brain area.

Conclusion

Our study reveals distinct histological patterns of S100B immunoeactive glia in two schizophrenia subtypes. This may be indicative of a heterogenic pathophysiology or distinct compensatory abilities: Astro-/oligodendroglial activation may result in increased cellular S100B in paranoid schizophrenia. On the contrary, residual schizophrenia may be caused by white matter oligodendroglial damage or dysfunction, associated with a release of S100B into body fluids.

Introduction

The hypothesis that S100B may play a role in the pathophysiology of schizophrenia is based on several studies demonstrating increased levels of S100B in the peripheral blood or cerebrospinal fluid (CSF) of schizophrenic patients (Lara et al., 2001, Ling et al., 2007, Rothermundt et al., 2001, Rothermundt et al., 2004a, Rothermundt et al., 2004b, Sarandol et al., 2007, Schmitt et al., 2005, Schroeter et al., 2003, Steiner et al., 2006a, Wiesmann et al., 1999). A review of these very consistent findings is given by van Beveren et al. (2006). Concentrations of S100B in serum were found to be tightly correlated with those in CSF of healthy people and schizophrenic patients (Nygaard et al., 1997, Rothermundt et al., 2004a). Additionally, the association of schizophrenia with certain S100B haplotypes has been observed, which leads to a tendency for increased S100B expression (Liu et al., 2005). It remains unclear, however, if increased levels of S100B in body fluids should be considered a pathogenetic or compensatory effect of schizophrenia, or whether it is simply an epiphenomenon.

The S100B protein is a Ca2+, Cu2+ and Zn2+ binding member of the S100-calmodulin–troponin superfamily and is primarily found in high abundance within the nervous system (Moore, 1965). S100B is not only implicated in the regulation of growth-associated intracellular processes, but is also a secretory protein and exhibits cytokine-like activities, mediating the interactions among glial cells and between glial cells and neurones. These effects are transduced, in part, by the receptor for advanced glycation end products (RAGE) and nuclear factor kappa B (NFκB) (Donato, 2001, Lam et al., 2001).

S100B acts in a dose-dependent manner on neuronal cultures (van Eldik and Wainwright, 2003). Nanomolar levels stimulate neurite growth and promote neuronal survival. However, micromolar levels result in opposite effects and can induce neuronal apoptosis. Furthermore, Whitaker-Azmitia et al. observed a similar effect on transgenic mice overexpressing S100B, which showed a significant loss of dendrites compared to controls (Whitaker-Azmitia et al., 1997). Several recent post-mortem-studies on patients with schizophrenia reported that there is indeed an indication for a reduction of neuropil in schizophrenia which may be progressive over time (Selemon et al., 2003). In conclusion, one might speculate on a causal link between elevated S100B levels and the above mentioned alterations of neuropil in schizophrenia.

Elevated levels of S100B in body fluids have often been considered a biomarker for astrocytic damage or dysfunction in schizophrenia (Rothermundt et al., 2001, Rothermundt et al., 2004a, Rothermundt et al., 2004b, Schroeter et al., 2003, Wiesmann et al., 1999). However, this assumption has not been proven yet, as no findings have been published on the cellular distribution of S100B in the brain of schizophrenic patients. Several investigators observed an association between increased S100B serum levels especially with either acute stages of schizophrenia (Lara et al., 2001, Rothermundt et al., 2004a, Sarandol et al., 2007, Steiner et al., 2006a) or with the development of deficit symptoms (Rothermundt et al., 2001, Rothermundt et al., 2004b, Sarandol et al., 2007, Schroeter et al., 2003). Thus, the cellular localization of S100B has been analyzed in patients with paranoid versus residual schizophrenia in the present study to reveal potentially relevant distinct compensatory/pathogenetic mechanisms.

It is noteworthy that S100B has also been detected outside the central nervous system, e.g. in adipose tissue, lymphocytes, melanocytes, the myocardium, vascular endothelial/smooth muscle cells, satellite cells of dorsal root ganglia, and Schwann cells of the peripheral nervous system (Steiner et al., 2007). In addition, the localization of S100B-immunoreactivity in many neural cell-types, including oligodendrocytes, O2A glial progenitor cells, ependymal cells, the choroid plexus epithelium, and a few neurones has been observed in normal human brain tissue (Steiner et al., 2007). Thus, S100B is not brain- or astrocyte-specific and the above mentioned studies on S100B levels in schizophrenia should be carefully interpreted to avoid misidentification of the involved cell type.

The aim of the present histological study was to compare the S100B-immunopositive glial cell-density between individuals with schizophrenia and controls and also between individuals with paranoid/residual subtypes of schizophrenia. We hypothesized that a loss or activation of S100B containing glia would be reflected by numerical differences between these diagnostic groups or diagnostic subgroups of schizophrenia. Telencephalic and diencephalic brain regions (including white matter), which are particularly relevant to schizophrenia, were investigated.

Section snippets

Human brain tissue

All brains were obtained from the Magdeburg Brain Collection. Collection of human brain material was performed in accordance with German laws and the local ethics committee. Written consent was obtained from the next of kin. The post-mortem brain tissue of 18 patients with schizophrenia (mean age 54 years; 9 males, 9 females) and 16 neuropsychiatric healthy control subjects (mean age 56 years; 7 males, 9 females) were used for the present study. Patients and healthy control subjects died

Descriptive statistics of the sample

There were no differences between the diagnostic subgroups regarding age (F(2, 31) = 0.346, P = 0.710), duration of illness (F(1, 16) = 0.502, P = 0.489) and autolysis time (F(2, 31) = 1.686, P = 0.202) (see Table 1).

S100B immunohistochemistry

Cells with an astrocytic morphology were primarily detected in the human neocortex and the pyramidal layer of the hippocampus. However, in the white matter and alveus of the hippocampus, most immunostained cells showed oligodendrocytic morphology (Fig. 1). The highest density of

Discussion

Several studies revealed increased levels of S100B in peripheral blood and CSF of patients with schizophrenia (Lara et al., 2001, Ling et al., 2007, Rothermundt et al., 2001, Rothermundt et al., 2004a, Rothermundt et al., 2004b, Schmitt et al., 2005, Schroeter et al., 2003, Steiner et al., 2006a, Wiesmann et al., 1999). In this context, it was postulated that increased S100B levels may indicate changes of pathophysiological significance to the brain tissue, in general, and to astrocytes, in

Role of funding source

Funding for this study was provided by the Saxony-Anhalt Ministry of Research (XN3594O/0405 M, N2-OGU), German Ministry of Research (BMBF-NBL3 01ZZ0107, BrainNet) and Stanley Foundation (07R-1832). These sponsors had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors

JS, HGB and BB conceived and designed the study. JS interpreted the results and drafted the manuscript together with AMM and TG. HB documented the results and contributed to the interpretation of results. NF and JW evaluated the slides. HD performed the statistical analysis. RB created the figures. CM performed the neuropathological examination of all cases. All authors contributed to and have approved the final manuscript.

Conflict of interest

All authors declare that they have no conflicts of interest.

Acknowledgements

The Saxony-Anhalt Ministry of Research (XN3594O/0405M, N2-OGU), German Ministry of Research (BMBF-NBL3 01ZZ0107, BrainNet) and Stanley Foundation (07R-1832) supported the present study. Iris Bertram, Sieglinde Funke, Gabriela Meyer-Lotz and Renate Stauch provided excellent technical assistance.

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