Glial cell activation in a subgroup of patients with schizophrenia indicated by increased S100B serum concentrations and elevated myo-inositol

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Abstract

Post-mortem and in-vivo studies support the hypothesis that astrocytes might be involved in the pathogenesis of schizophrenia. To further substantiate this hypothesis two markers of astroglial activation (myo-inositol, S100B) acquired with independent methods (1H-MRS, quantitative immunoassay) were concomitantly measured in schizophrenic patients. Patients with increased S100B levels showed elevated myo-inositol concentrations. This pilot study demonstrates a concomitant elevation of two markers indicating astrocyte activation in a subgroup of schizophrenic patients.

Introduction

Until recently, astrocytes were regarded as mere metabolic supporters of neurons. However, several lines of research indicate that astrocyte dysfunction can be directly responsible for neuronal malfunction mainly via glutamate-induced Ca2+ modulation (Araque et al., 1999, Grosche et al., 1999) and might therefore even play a key role in the development of schizophrenia. Recent studies demonstrated an astroglial loss in schizophrenia (Cotter et al., 2001, Rajkowska et al., 2002) rather than increased astrogliosis (Harrison, 1999). There are signs of dystrophic changes with decreased intact mitochondria in astrocytes (Uranova et al., 1996) and astroglial function after injury has been shown to be impaired in the brains of patients with schizophrenia (Niizato et al., 2001).

The astrocytic protein S100B is an indicator of astroglial function exerting paracrine and autocrine effects on neurons and glia. From in-vitro and in-vivo animal experiments it is known that S100B modulates the balance between cell proliferation and differentiation. Those effects appear to be mediated primarily via inhibition of the phosphorylation of key synaptic proteins (Rothermundt et al., 2003).

In schizophrenia, several studies have demonstrated increased S100B cerebrospinal fluid (CSF) and serum concentrations in the acute stage of the disease (Lara et al., 2001, Rothermundt et al., 2004a, Schroeter et al., 2003). High concentrations were associated with negative or deficit symptoms and patients with high S100B serum levels showed slower psychopathological improvement upon treatment than schizophrenics with normal S100B concentrations (Rothermundt et al., 2004b).

Myo-insositol as part of a second messenger system triggering the release of Ca2 in mitochondria and endoplasmatic reticulum can also be regarded as a marker of astroglial activity (Malhi et al., 2002). Most spectroscopy studies reported unchanged myo-inositol concentrations in different brain regions in schizophrenic patients (Keshavan et al., 2000) whereas in the parietal white matter increased myo-inositol levels were reported (Auer et al., 2001).

To further understand the potential role of astrocytes in the pathogenesis of schizophrenia and the functional relevance of elevated serum S100B concentrations, S100B measurements were combined with high-resolution magnetic resonance spectroscopy (MRS) investigation of myo-inositol.

Section snippets

Methods

After written informed consent according to the standards of the Declaration of Helsinki was acquired, blood samples (9 ml) were taken by venipuncture from N = 12 inpatients (11 males, 1 female; mean age 25.33 ± 4.75 years, range 21–34 years; 9 drug naïve, 2 on olanzapine, 1 on clozapine) suffering from an acute schizophrenic episode (paranoid subtype) and N = 12 age- and sex-matched healthy controls (11 males, 1 female; mean age 25.33 ± 4.75 years, range 21–34 years). The German version of the

Results

The schizophrenic patients presented a significantly higher mean serum S100B concentration than matched healthy controls (Table 1).

Patients with S100B levels higher than the mean plus two standard deviations (SD) of the control group (0.054 μg/L) were assigned to group H (“high”; n = 6), the remaining patients with S100B concentration lower than 0.054 μg/L formed group L (“low”; n = 6). Both groups did not differ concerning age (group H: 23.8 ± 4.4 years; group L: 26.8 ± 4.9 years; T =  1.1, df = 10, p = 

Discussion

In this pilot study schizophrenic patients with increased S100B serum concentration showed higher in-vivo brain myo-inositol values as measured by MRS compared to patients with normal S100B levels. This finding supports the hypothesis that activation of astrocytes may play an important role in the pathogenesis of schizophrenia at least in a subgroup of patients. In healthy controls and patients with normal S100B, however, a correlation between S100B and myo-inositol could not be demonstrated.

Conclusions

A concomitant upregulation of the two markers of astrocyte activity S100B and myo-inositol in a subgroup of patients with schizophrenia supports the hypothesis that astrocytes might be involved in the pathogenesis of this disorder. Studies with larger samples and longitudinal designs are needed to further clarify the significance of astrocyte activity and its clinical concomitants in schizophrenia.

Acknowledgement

This study was supported by an Innovative Medical Research grant (IMF) of the University of Muenster to MR (RO 219919).

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    Citation Excerpt :

    However, the consensus is that glial damage is suspected given the increase in astrocyte concentration in patients with schizophrenia. Schizophrenia patients also appear to have hyper-functioning astrocytes, measured by increases in the astrocyte marker S100B and glial cell activation (Rothermundt et al., 2007). The strongest supporting evidence comes from the modulation of glutamate metabolism by astrocytes (Steiner et al., 2008a, 2011b).

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