Epub – Biological Psychiatry
Localization and diagnostic specificity of glutamic acid decarboxylase transcript alterations in the dorsolateral prefrontal cortex in schizophrenia

Dowling KF, Dienel SJ, Barile Z, Bazmi HH, Lewis DA

Background: 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 two enzymes, GAD67 and GAD65, which mediate basal and activity-dependent GABA 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.
Methods: Levels of GAD67 and GAD65 mRNAs in superficial (layers 2/superficial 3) and deep (deep layer 6/white matter) zones of the DLPFC were quantified by qPCR in schizophrenia (n=41), major depression (n=42), bipolar disorder (n=39), and unaffected comparison (UC; n=43) subjects.
Results: Relative to the UC group, GAD67 and GAD65 mRNA levels in schizophrenia were lower (p=0.039, effect size (ES)=-0.69 and p=0.027, ES=-0.72, respectively) in the superficial zone but were unaltered in the deep zone. In major depression, only GAD67 mRNA levels were lower, and only in the superficial zone (p=0.089, ES=0.70). No differences were detected in bipolar disorder. Neither GAD67 nor GAD65 mRNA alterations were explained by psychosis, mood disturbance or common comorbid factors.
Conclusions: 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.

Dowling KF, Dienel SJ, Barile Z, Bazmi HH, Lewis DA. Localization and diagnostic specificity of glutamic acid decarboxylase transcript alterations in the dorsolateral prefrontal cortex in schizophrenia. Biol Psychiatry. 2023 Apr 13:S0006-3223(23)01199-X. doi: 10.1016/j.biopsych.2023.04.003. [Epub ahead of print]. PubMed PMID: 37061080.

https://pubmed.ncbi.nlm.nih.gov/37061080/