Elsevier

Schizophrenia Research

Volume 52, Issues 1–2, 1 October 2001, Pages 101-105
Schizophrenia Research

Low GSK-3 activity in frontal cortex of schizophrenic patients

https://doi.org/10.1016/S0920-9964(00)00174-2Get rights and content

Abstract

Glycogen synthase kinase-3 (GSK-3) (EC 2.7.1.37) is a protein kinase highly abundant in brain and involved in signal transduction cascades of multiple cellular processes, particularly neurodevelopment. Two forms of the enzyme, GSK-3α and -3β have been previously identified. We have previously reported reduced GSK-3β protein levels in postmortem frontal cortex of schizophrenic patients. In an attempt to explore whether reduction of GSK-3β levels is brain region specific we examined it in occipital cortex. In order to find out if the reduction in frontal cortex is reflected in altered activity we measured GSK-3 enzymatic activity in this brain region. Western-blot analysis of GSK-3β was carried out in postmortem occipital cortex of 15 schizophrenic, 15 bipolar, and 15 unipolar patients, and 15 normal controls. GSK-3 activity was measured by quantitating the phosphorylation of the specific substrate phospho-CREB in the frontal cortex specimens. GSK-3β levels in occipital cortex did not differ between the four diagnostic groups. GSK-3 activity in the frontal cortex of schizophrenic patients was 45% lower than that of normal controls (0.196±0.082 and 0.357±0.084pmol/mg protein×min, respectively; Kruskal–Wallis analysis: chi-square=8.27, df=3, p=0.04). The other two diagnostic groups showed no difference from the control group. Our results are consistent with the notion that schizophrenia involves neurodevelopmental pathology.

Introduction

The neurodevelopmental hypothesis of schizophrenia proposes that orderly brain development is affected by an as yet unidentified event occurring during pregnancy or at early postnatal period (Altshuler et al., 1987, Arnold et al., 1991a, Conrad and Scheibel, 1987). Although the presence of cytoarchitectural abnormalities in schizophrenia has been documented (for review see Weinberger, 1996, Arnold, 1999, Bunney et al., 1995, Chua and Murray, 1996, Hudson et al., 1993) the underlying molecular mechanisms causing these features remain unclear.

The Wnt family of genes is central to normal brain development (Cotter et al., 1998). Cell activation by Wnt leads to the inactivation of glycogen synthase kinase-3β (GSK-3β). This in turn allows the accumulation of β-catenin, which translocates to the nucleus where it interacts with neuronal transcription factors (Moon et al., 1997). Wnt-7a, through GSK-3β, was found to regulate axonal remodeling in developing cerebellar neurons (Lucas et al., 1998). There are reports of increased Wnt-1 expression in hippocampus (Miyaoka et al., 1999), and reduced levels of α- and β-catenin in the hippocampus and subiculum of schizophrenic patients (Cotter et al., 1998).

GSK-3α, reported to be reduced in lymphocytes of schizophrenic patients (Yang et al., 1995) is a regulatory enzyme of some neuronal proteins implicated in maldevelopment and in schizophrenia (Yang et al., 1995, Browning et al., 1993, Mackie et al., 1989, van Kammen et al., 1998, Arnold et al., 1991b, Cotter et al., 1997, Garcia-Perez et al., 1998).

Programmed cell death is an essential component of normal brain development. Over-expression of GSK-3β was recently found to facilitate induced apoptosis in human SH-SY5Y neuroblastoma cells (Bijur et al., 2000) and phosphorylation of β-catenin by GSK-3β increases neuronal vulnerability to apoptosis induced by amyloid-β protein (Zhang et al., 1998).

We have found 41% lower GSK-3β protein levels in postmortem frontal cortex of schizophrenic patients compared with those of unipolar and bipolar patients and normal controls (Kozlovsky et al., 2000). In the present study we aimed to test whether low GSK-3β protein levels are brain-region specific. We thus measured GSK-3β protein levels in occipital cortex postmortem specimens derived from schizophrenic, bipolar and unipolar patients and control subjects. To test whether low frontal GSK-3β levels result in low enzymatic activity, we measured GSK-3 activity in the same frontal cortex specimens that were used for quantifying GSK-3β protein levels (Kozlovsky et al., 2000).

Section snippets

Postmortem brain samples

Frozen postmortem brain samples of occipital cortex and frontal cortex (BA 10) were obtained from the Stanley Foundation Brain Bank. The 60 samples consisted of 15 schizophrenic patients, 15 bipolar patients, 15 unipolar patients and 15 normal controls, nine males and six females in each diagnostic group. Two frontal cortex specimens (one male control and one male schizophrenic) were lost before the present study was initiated. The four groups were matched for age, sex, race, postmortem

GSK-3β protein levels in occipital cortex

There was no difference in occipital cortex GSK-3β protein levels among control subjects, unipolar, bipolar and schizophrenic patients (n=15 each), which exhibited 290±30, 275±36, 287±34, 243±33μunits (mean±SEM), respectively. Two-way ANOVA for diagnosis and sex revealed no difference between the diagnostic groups, no difference between male and female values and no interaction. There was no significant correlation between GSK-3β protein levels and any demographic parameter including age, sex

Discussion

The present study demonstrates no differences in GSK-3β protein levels between postmortem occipital cortex specimens from schizophrenic, bipolar and unipolar patients and normal controls. Thus, the reduction in GSK-3β in frontal cortex of schizophrenic patients (Kozlovsky et al., 2000) does not represent a general alteration in GSK-3β protein levels in the brain of schizophrenic patients. Levels of other neuronal-specific molecules (synaptophysin and GAP-43) are also found altered in prefrontal

Acknowledgements

Postmortem brains were donated by the Stanley Foundation Brain Consortium courtesy of Drs Llewellyn B. Bigelow, Juraj Cervenak, Mary M. Herman, Thomas M. Hyde, Joel E. Kleinman, Jose D. Paltan, Robert M. Post, E. Fuller Torrey, Maree J. Webster, and Robert H. Yolken. Dr Nitsan Kozlovsky is a Leah Smith Postdoctoral Fellow of the National Institute for Psychobiology in Israel.

References (30)

  • L.L. Altshuler et al.

    Hippocampal pyramidal cell orientation in schizophrenia

    Arch. Gen. Psychiatry

    (1987)
  • S.E. Arnold

    Neurodevelopmental abnormalities in schizophrenia: insights from neuropathology

    Dev. Psychopathol.

    (1999)
  • S.E. Arnold et al.

    Some cytoarchitectural abnormalities of the entorhinal cortex in schizophrenia

    Arch. Gen. Psychiatry

    (1991)
  • S.E. Arnold et al.

    Abnormal expression of two microtubule-associated proteins (MAP2 and MAP5) in specific subfields of the hippocampal formation in schizophrenia

    Proc. Natl Acad. Sci. USA

    (1991)
  • B.G. Bunney et al.

    New morphological and neuropathological findings in schizophrenia: a neurodevelopmental perspective

    Clin. Neurosci.

    (1995)
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