|Cognitive deficits in schizophrenia are associated with altered activity of the dorsolateral prefrontal cortex (DLPFC) which has been attributed to lower expression of the 67 kDa isoform of glutamic acid decarboxylase (GAD67), the major GABA-synthesizing enzyme. However, little is known about the relationship of prefrontal GAD67 mRNA levels and illness severity, translation of the transcript into protein, or protein levels in axon terminals, the key site of GABA production and function. Quantitative PCR was used to measure GAD67 mRNA levels in the DLPFC from 42 subjects with schizophrenia and 42 matched comparison subjects. Western blotting was used to quantify tissue levels of GAD67 protein in a subset of subjects where potential confounds of protein measures were controlled. Multi-label, confocal immunofluorescence was used to quantify GAD67 protein levels in the axon terminals of parvalbumin-containing GABA neurons, known to have low levels of GAD67 mRNA in schizophrenia. GAD67 mRNA levels were significantly 15% lower in schizophrenia subjects, but transcript levels were not associated with predictors or measures of disease severity or chronicity. In schizophrenia subjects, GAD67 protein levels were significantly 10% lower in total gray matter and 49% lower in parvalbumin axon terminals. These findings indicate that lower GAD67 mRNA expression is common in schizophrenia, is not a consequence of having the illness, and leads to less translation of the protein, especially in the axon terminals of parvalbumin-containing neurons. As summarized in the figure, lower synthesis of GABA (red dots) in parvalbumin neurons is thought to lead to impaired inhibition of DLPFC pyramidal neurons reduced gamma band power, and impaired cognition in schizophrenia.
|Curley AA, Arion D, Volk DW, Asafu-Adjei JK, Sampson AR, Fish KN, Lewis DA: Cortical deficits of glutamic acid decarboxylase 67 expression in schizophrenia: Clinical, protein, and cell type-specific features.Am J Psychiatry, 168:921-929, 2011.