Cortical Deficits of Glutamic Acid Decarboxylase 67 Expression in Schizophrenia: Clinical, Protein, and Cell Type-Specific Features

• Published in: The American journal of psychiatry Vol. 168; no. 9; pp. 921 - 929
• Main Authors: Curley, Allison A., Arion, Dominique, Volk, David W., Asafu-Adjei, Josephine K., Sampson, Allan R., Fish, Kenneth N., Lewis, David A.
• Format: Journal Article
• Language: English
• Published: Arlington, VA American Psychiatric Publishing 01.09.2011; American Psychiatric Association
• Subjects: Adult; Adult and adolescent clinical studies; Biological and medical sciences; Blotting, Western; Brain; Cognition & reasoning; Cognition Disorders - genetics; Cognition Disorders - pathology; Cohort Studies; Enzymes; Female; gamma-Aminobutyric Acid - metabolism; Gene expression; Glutamate Decarboxylase - genetics; Humans; Male; Medical sciences; Microscopy, Fluorescence; Middle Aged; Neurons - metabolism; Neurons - pathology; Neuropsychology; Parvalbumins - metabolism; Prefrontal Cortex - enzymology; Prefrontal Cortex - pathology; Presynaptic Terminals; Proteins; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Reference Values; RNA, Messenger - genetics; Schizophrenia; Schizophrenia - genetics; Schizophrenia - pathology; Psychosis; Carbon-carbon lyases; Enzyme; Carboxy-lyases; Schizophrenia; Lyases; Glutamate decarboxylase; Protein
• ISSN: 0002-953X; 1535-7228; 1535-7228
• DOI: 10.1176/appi.ajp.2011.11010052

Depression was associated with increased inflammation as measured by elevated levels of interleukin-6 and high-sensitivity C-reactive protein in patients with coronary heart disease, which was accounted for by the increased body mass index and cigarette smoking associated with depression. Objective:Cognitive deficits in schizophrenia are associated with altered activity of the dorsolateral prefrontal cortex, which has been attributed to lower expression of the 67 kDa isoform of glutamic acid decarboxylase (GAD67), the major γ-aminobutyric acid (GABA)-synthesizing enzyme. However, little is known about the relationship of prefrontal GAD67 mRNA levels and illness severity, translation of the transcript into protein, and protein levels in axon terminals, the key site of GABA production and function. Method:Quantitative polymerase chain reaction was used to measure GAD67 mRNA levels in postmortem specimens of dorsolateral prefrontal cortex from subjects with schizophrenia and matched comparison subjects with no known history of psychiatric or neurological disorders (N=42 pairs). In a subset of this cohort in which potential confounds of protein measures were controlled (N=19 pairs), Western blotting was used to quantify tissue levels of GAD67 protein in tissue. In five of these pairs, multilabel confocal immunofluorescence was used to quantify GAD67 protein levels in the axon terminals of parvalbumin-containing GABA neurons, which are known to have low levels of GAD67 mRNA in schizophrenia. Results:GAD67 mRNA levels were significantly lower in schizophrenia subjects (by 15%), but transcript levels were not associated with predictors or measures of illness severity or chronicity. In schizophrenia subjects, GAD67 protein levels were significantly lower in total gray matter (by 10%) and in parvalbumin axon terminals (by 49%). Conclusions:The findings that lower GAD67 mRNA expression is common in schizophrenia, that it is not a consequence of having the illness, and that it leads to less translation of the protein, especially in the axon terminals of parvalbumin-containing neurons, support the hypothesis that lower GABA synthesis in parvalbumin neurons contributes to dorsolateral prefrontal cortex dysfunction and impaired cognition in schizophrenia.