Elsevier

Schizophrenia Research

Volume 69, Issues 2–3, 1 August 2004, Pages 317-323
Schizophrenia Research

Glial fibrillary acidic protein is reduced in cerebellum of subjects with major depression, but not schizophrenia

https://doi.org/10.1016/j.schres.2003.08.014Get rights and content

Abstract

Glial fibrillary acidic protein (GFAP) is a major protein of astrocyte intermediate filaments and a specific marker for astrocytes. Alterations in levels of GFAP may reflect pathological regulation of neuronal function and survival as well as abnormal synaptogenesis and neurotransmission. We employed quantitative gel electrophoresis and Western blotting to measure levels of GFAP in cerebella of 60 subjects divided equally among schizophrenia, bipolar disorder, major depression, and normal controls. GFAP levels were reduced by 32%, 17% and 14.5% in depressed, bipolar, and schizophrenic cerebella, respectively, versus controls. Only the depressed value was significantly different (p=0.015 Post-hoc Bonferroni test). Measurement of β-actin levels showed no differences between the various groups. No significant effects of confounding variables were found. This is the first demonstration of GFAP reductions in cerebellum of subjects with mood disorders and schizophrenia, thereby adding to the reports of reductions in GFAP/glial cell counts in other brain regions of subjects with major depression, thus suggesting a downregulation of glial function in this disorder.

Introduction

A number of recent reports Bowley et al., 2002, Rajkowska et al., 2002, Cotter et al., 2001, Miguel-Hidalgo et al., 2000, Rajkowska et al., 1999, Webster et al., 2001, Johnston-Wilson et al., 2000, Ongur et al., 1998 indicate reductions in glial cell number in different areas of the brain in subjects with mood disorders and schizophrenia. Glial cells have important functions, which impact neuronal cell health and integrity (Coyle and Schwarcz, 2000). Glial fibrillary acidic protein (GFAP) is a major protein of astrocyte intermediate filaments and a specific marker for astrocytes Patanow et al., 1997, Montgomery, 1994. GFAP production begins as early as 25 weeks after conception in normal human astrocytes and as early as 15 weeks in ependymal cells following brain damage Cohen and Rossmann, 1994, Rossmann et al., 1980 in utero. Astrocytes bearing GFAP immunoreactivity serve many functions in health and disease including guidance of neuronal migration, production of extracellular matrix proteins and adhesion molecules Coyle and Schwarcz, 2000, Fatemi et al., 2002a, Fatemi et al., 2002b, production of neurite promoting factors, cerebral angiogenesis, neurotransmission, regulation of pH and ion concentration, phagocytosis, glutathione production and neuroendocrine functions (Coyle and Schwarcz, 2000). Astrocytes have been implicated in metabolic roles such as uptake of glucose and glutamate, storage of glycogen and clearance of K. While increases in GFAP production may be a sign of astrogliosis, reactive injury, and even neurodegeneration Coyle and Schwarcz, 2000, Fatemi et al., 2002a, Fatemi et al., 2002b, decreases in its levels may signify overall reductions in synaptic capabilities of neurons Rajkowska et al., 2002, Moises et al., 2002.

Cerebellum is an important brain area which is involved in processing of higher order cortical activity and involved in pathology of several neurodevelopmental disorders (Fatemi et al., 2001). Ample evidence indicates that a dysfunctional corticocerebellar circuit may be operational in schizophrenic patients leading to what Andreasen and colleagues have called “cognitive dysmetria” being the cause of schizophrenic symptoms (Wiser et al., 1998). We investigated the production of GFAP by glial cells in mood disorders and schizophrenia using the well-characterized Stanley brain collection (Torrey et al., 2000).

Section snippets

Specimen collection

Human cerebellar specimens (lateral cerebellum) were obtained from the Stanley Foundation Brain Consortium (Torrey et al., 2000). The sample consisted of 60 subjects (15 normal controls, 15 depressed patients, 15 schizophrenic, and 15 bipolar patients) whose brains have been studied previously by us (Fatemi et al., 2000) and numerous other investigators Cotter et al., 2001, Webster et al., 2001, Johnston-Wilson et al., 2000, Knable et al., 2002. Psychiatric diagnoses had been made according to

Results

There were significant between-group differences in only two of the confounders and cerebellar GFAP and β-actin levels: 1) freezer storage time and bipolar group versus controls (p=0.01) and schizophrenic group versus controls (p=0.01); however, this confounder had no significant effect on either GFAP or β-actin levels; 2) age of onset and depression versus bipolar group (p=0.008) and depression versus schizophrenic group (p=0.02), again, there was no significant effect of this confound on

Discussion

This report is the first demonstration of significant reductions in the levels of GFAP in cerebella of subjects with major depression (p<0.015) and reductions (nonsignificant) in bipolar disorder and schizophrenia. Reduction in levels of GFAP may subserve synaptic dysfunction and abnormal neurotransmission in brains of subjects with major depression and potentially bipolar disorder and schizophrenia. Several previous studies using various methodologies showed glial dysfunction in all three

Acknowledgments

Supported by the Stanley Foundation grant (SHF) and the Stanley Scholar program (SCS). We are grateful to the Stanley Foundation Neuropathology Consortium Brain Bank for provision of brain samples courtesy of Drs. M. Knable, E.F. Torrey, M.J. Webster, S. Weiss and R.H. Yolken. We appreciate the secretarial assistance of Mr. Jeremy Bohrer and Ms. Janet Holland.

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