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.
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 beta-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. beta-Actin levels did not vary significantly between groups. There were no significant effects of confounding variables on levels of various proteins.


CONCLUSIONS
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.
Fatemi
S Hossein
SH
Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, MMC #392, 420 Delaware Street SE, Minneapolis, MN 55455, USA. fateM002@umn.edu
Hossein Fatemi
S
S
Stary
Joel M
JM
Earle
Julie A
JA
Araghi-Niknam
Mohsen
M
Eagan
Elisabeth
E
D000328:Adult; D000368:Aged; D001714:Bipolar Disorder / Q000134:cerebrospinal fluid / Q000503:physiopathology; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003710:Demography; D003863:Depression / Q000134:cerebrospinal fluid / Q000503:physiopathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D019964:Mood Disorders / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018079:Receptors, GABA / Q000378:metabolism*; D000091042:Reelin Protein; D012559:Schizophrenia / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000503:physiopathology*; D012697:Serine Endopeptidases / Q000378:metabolism*
D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D018079:Receptors, GABA; D000091042:Reelin Protein; C000717127:RELN protein, human; D012697:Serine Endopeptidases; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2