GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and Reelin proteins in cerebellum

S H Fatemi; Joel M. Stary; Julie A. Earle; Mohsen Araghi-Niknam; Elisabeth Eagan

doi:10.1016/j.schres.2004.02.017

GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and Reelin proteins in cerebellum

S H Fatemi, Joel M. Stary, Julie A. Earle, Mohsen Araghi-Niknam, Elisabeth Eagan

Psychiatry & Behavioral Sciences

Research output: Contribution to journal › Article › peer-review

239 Scopus citations

Abstract

Background: Glutamic acid decarboxylase (GAD) is the rate limiting enzyme responsible for conversion of glutamate to gamma-aminobutyric acid (GABA) regulating levels of glutamate and GABA in the mammalian brain. Reelin is an extracellular matrix protein that helps in normal lamination of the embryonic brain and subserves synaptic plasticity in adult brain. Both GAD and Reelin are colocalized to the same GABAergic interneurons in several brain sites. We hypothesized that levels of GAD and Reelin would be altered in cerebellum of subjects with schizophrenia and mood disorders differentially vs. controls. Methods: We employed SDS-PAGE and Western blotting to measure levels of GAD isomers 65 and 67 kDa and Reelin isoforms 410-, 330- and 180-kDa proteins as well as β-actin in cerebellum of subjects with schizophrenia, bipolar disorder and major depression vs. controls (N=15 per group). Results: GAD 65- and 67-kDa levels were decreased significantly in bipolar, depressed and schizophrenic subjects (p<0.05) vs. controls. Reelin 410- and 180-kDa proteins decreased significantly (p<0.05) in bipolar subjects vs. controls. Reelin 180 kDa was decreased significantly (p<0.05) in schizophrenics vs. controls. β-Actin levels did not vary significantly between groups. There were no significant effects of confounding variables on levels of various proteins. Conclusion: This study demonstrates for the first time significant deficits in GABAergic markers Reelin and GAD 65 and 67 proteins in bipolar subjects and global deficits in the latter proteins in schizophrenia and mood disorders, accounting for the reported alterations in CSF/plasma levels of glutamate and GABA in these disorders.

Original language	English (US)
Pages (from-to)	109-122
Number of pages	14
Journal	Schizophrenia Research
Volume	72
Issue number	2-3
DOIs	https://doi.org/10.1016/j.schres.2004.02.017
State	Published - Jan 1 2005

Bibliographical note

Funding Information:
Postmortem brains were donated by The Stanley Medical Research Institute’s Brain Collection courtesy of Drs. Michael B. Knable, E. Fuller Torrey, Maree J. Webster, Serge Weis, and Robert H. Yolken. SHF is supported by the Stanley Medical Research Institute. We are grateful to Dr. A. Goffinet for his generous gift of anti-Reelin antibody. We appreciate the secretarial help provided by Ms. Janet Holland and Ms. Laurie Iverson.

Keywords

Bipolar disorder
Cerebellum
GAD 65 & 67 kDa proteins
Major depression
Postmortem
Reelin
Schizophrenia
Western blotting

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10.1016/j.schres.2004.02.017

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title = "GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and Reelin proteins in cerebellum",

abstract = "Background: Glutamic acid decarboxylase (GAD) is the rate limiting enzyme responsible for conversion of glutamate to gamma-aminobutyric acid (GABA) regulating levels of glutamate and GABA in the mammalian brain. Reelin is an extracellular matrix protein that helps in normal lamination of the embryonic brain and subserves synaptic plasticity in adult brain. Both GAD and Reelin are colocalized to the same GABAergic interneurons in several brain sites. We hypothesized that levels of GAD and Reelin would be altered in cerebellum of subjects with schizophrenia and mood disorders differentially vs. controls. Methods: We employed SDS-PAGE and Western blotting to measure levels of GAD isomers 65 and 67 kDa and Reelin isoforms 410-, 330- and 180-kDa proteins as well as β-actin in cerebellum of subjects with schizophrenia, bipolar disorder and major depression vs. controls (N=15 per group). Results: GAD 65- and 67-kDa levels were decreased significantly in bipolar, depressed and schizophrenic subjects (p<0.05) vs. controls. Reelin 410- and 180-kDa proteins decreased significantly (p<0.05) in bipolar subjects vs. controls. Reelin 180 kDa was decreased significantly (p<0.05) in schizophrenics vs. controls. β-Actin levels did not vary significantly between groups. There were no significant effects of confounding variables on levels of various proteins. Conclusion: This study demonstrates for the first time significant deficits in GABAergic markers Reelin and GAD 65 and 67 proteins in bipolar subjects and global deficits in the latter proteins in schizophrenia and mood disorders, accounting for the reported alterations in CSF/plasma levels of glutamate and GABA in these disorders.",

keywords = "Bipolar disorder, Cerebellum, GAD 65 & 67 kDa proteins, Major depression, Postmortem, Reelin, Schizophrenia, Western blotting",

author = "Fatemi, {S H} and Stary, {Joel M.} and Earle, {Julie A.} and Mohsen Araghi-Niknam and Elisabeth Eagan",

note = "Funding Information: Postmortem brains were donated by The Stanley Medical Research Institute{\textquoteright}s Brain Collection courtesy of Drs. Michael B. Knable, E. Fuller Torrey, Maree J. Webster, Serge Weis, and Robert H. Yolken. SHF is supported by the Stanley Medical Research Institute. We are grateful to Dr. A. Goffinet for his generous gift of anti-Reelin antibody. We appreciate the secretarial help provided by Ms. Janet Holland and Ms. Laurie Iverson. ",

year = "2005",

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doi = "10.1016/j.schres.2004.02.017",

language = "English (US)",

volume = "72",

pages = "109--122",

journal = "Schizophrenia Research",

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TY - JOUR

T1 - GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and Reelin proteins in cerebellum

AU - Fatemi, S H

AU - Stary, Joel M.

AU - Earle, Julie A.

AU - Araghi-Niknam, Mohsen

AU - Eagan, Elisabeth

N1 - Funding Information: Postmortem brains were donated by The Stanley Medical Research Institute’s Brain Collection courtesy of Drs. Michael B. Knable, E. Fuller Torrey, Maree J. Webster, Serge Weis, and Robert H. Yolken. SHF is supported by the Stanley Medical Research Institute. We are grateful to Dr. A. Goffinet for his generous gift of anti-Reelin antibody. We appreciate the secretarial help provided by Ms. Janet Holland and Ms. Laurie Iverson.

PY - 2005/1/1

Y1 - 2005/1/1

N2 - Background: Glutamic acid decarboxylase (GAD) is the rate limiting enzyme responsible for conversion of glutamate to gamma-aminobutyric acid (GABA) regulating levels of glutamate and GABA in the mammalian brain. Reelin is an extracellular matrix protein that helps in normal lamination of the embryonic brain and subserves synaptic plasticity in adult brain. Both GAD and Reelin are colocalized to the same GABAergic interneurons in several brain sites. We hypothesized that levels of GAD and Reelin would be altered in cerebellum of subjects with schizophrenia and mood disorders differentially vs. controls. Methods: We employed SDS-PAGE and Western blotting to measure levels of GAD isomers 65 and 67 kDa and Reelin isoforms 410-, 330- and 180-kDa proteins as well as β-actin in cerebellum of subjects with schizophrenia, bipolar disorder and major depression vs. controls (N=15 per group). Results: GAD 65- and 67-kDa levels were decreased significantly in bipolar, depressed and schizophrenic subjects (p<0.05) vs. controls. Reelin 410- and 180-kDa proteins decreased significantly (p<0.05) in bipolar subjects vs. controls. Reelin 180 kDa was decreased significantly (p<0.05) in schizophrenics vs. controls. β-Actin levels did not vary significantly between groups. There were no significant effects of confounding variables on levels of various proteins. Conclusion: This study demonstrates for the first time significant deficits in GABAergic markers Reelin and GAD 65 and 67 proteins in bipolar subjects and global deficits in the latter proteins in schizophrenia and mood disorders, accounting for the reported alterations in CSF/plasma levels of glutamate and GABA in these disorders.

AB - Background: Glutamic acid decarboxylase (GAD) is the rate limiting enzyme responsible for conversion of glutamate to gamma-aminobutyric acid (GABA) regulating levels of glutamate and GABA in the mammalian brain. Reelin is an extracellular matrix protein that helps in normal lamination of the embryonic brain and subserves synaptic plasticity in adult brain. Both GAD and Reelin are colocalized to the same GABAergic interneurons in several brain sites. We hypothesized that levels of GAD and Reelin would be altered in cerebellum of subjects with schizophrenia and mood disorders differentially vs. controls. Methods: We employed SDS-PAGE and Western blotting to measure levels of GAD isomers 65 and 67 kDa and Reelin isoforms 410-, 330- and 180-kDa proteins as well as β-actin in cerebellum of subjects with schizophrenia, bipolar disorder and major depression vs. controls (N=15 per group). Results: GAD 65- and 67-kDa levels were decreased significantly in bipolar, depressed and schizophrenic subjects (p<0.05) vs. controls. Reelin 410- and 180-kDa proteins decreased significantly (p<0.05) in bipolar subjects vs. controls. Reelin 180 kDa was decreased significantly (p<0.05) in schizophrenics vs. controls. β-Actin levels did not vary significantly between groups. There were no significant effects of confounding variables on levels of various proteins. Conclusion: This study demonstrates for the first time significant deficits in GABAergic markers Reelin and GAD 65 and 67 proteins in bipolar subjects and global deficits in the latter proteins in schizophrenia and mood disorders, accounting for the reported alterations in CSF/plasma levels of glutamate and GABA in these disorders.

KW - Bipolar disorder

KW - Cerebellum

KW - GAD 65 & 67 kDa proteins

KW - Major depression

KW - Postmortem

KW - Reelin

KW - Schizophrenia

KW - Western blotting

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JO - Schizophrenia Research

JF - Schizophrenia Research

IS - 2-3

ER -

GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and Reelin proteins in cerebellum

Abstract

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