Localization and Diagnostic Specificity of Glutamic Acid Decarboxylase Transcript Alterations in the Dorsolateral Prefrontal Cortex in Schizophrenia

• Published in: Biological psychiatry (1969) Vol. 94; no. 4; pp. 322 - 331
• Main Authors: Dowling, Kevin F., Dienel, Samuel J., Barile, Zackery, Bazmi, H. Holly, Lewis, David A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.08.2023
• Subjects: Bipolar disorder; DLPFC; Dorsolateral Prefrontal Cortex; GAD65; GAD67; gamma-Aminobutyric Acid; Glutamate Decarboxylase - genetics; Glutamate Decarboxylase - metabolism; Humans; Major depression; Prefrontal Cortex - metabolism; Psychiatric/Mental Health; RNA, Messenger; Schizophrenia; Schizophrenia - diagnosis; Schizophrenia - genetics; Schizophrenia; Bipolar disorder; DLPFC; GAD67; Major depression; GAD65
• DOI: 10.1016/j.biopsych.2023.04.003
• ISSN: 0006-3223; 1873-2402

Working memory (WM) deficits in schizophrenia are thought to reflect altered inhibition in the dorsolateral prefrontal cortex (DLPFC). This interpretation is supported by findings of lower transcript levels of the 2 enzymes, GAD67 and GAD65, which mediate basal and activity-dependent GABA (gamma-aminobutyric acid) synthesis, respectively. However, the relative magnitude, location within the depth of the DLPFC, and specificity to the disease process of schizophrenia of alterations in GAD67 and/or GAD65 remain unclear. Levels of GAD67 and GAD65 messenger RNAs (mRNAs) in superficial (layers 2/superficial 3) and deep (deep layer 6/white matter) zones of the DLPFC were quantified by quantitative polymerase chain reaction in subjects with schizophrenia (n = 41), major depression (n = 42), or bipolar disorder (n = 39) and unaffected comparison (n = 43) subjects. Relative to the unaffected comparison group, GAD67 and GAD65 mRNA levels in the schizophrenia group were lower (p = .039, effect size = −0.69 and p = .027, effect size = −0.72, respectively) in the superficial zone but were unaltered in the deep zone. In the major depression group, only GAD67 mRNA levels were lower and only in the superficial zone (p = .089, effect size = 0.70). No differences were detected in the bipolar disorder group. Neither GAD67 nor GAD65 mRNA alterations were explained by psychosis, mood disturbance, or common comorbid factors. Alterations in markers of GABA synthesis demonstrated transcript, DLPFC zone, and diagnostic specificity. Given the dependence of WM on GABA neurotransmission in the superficial DLPFC, our findings suggest that limitations to GABA synthesis in this location contribute to WM impairments in schizophrenia, especially during demanding WM tasks, when GABA synthesis requires the activity of both GAD67 and GAD65.