Lower Expression of Glutamic Acid Decarboxylase 67 in the Prefrontal Cortex of Subjects with Schizophrenia: Contribution of Altered Regulation by Zif268
Cognitive deficits of schizophrenia might be due, at least in part, to lower expression of the 67 kDa isoform of glutamic acid decarboxylase (GAD67), a key enzyme for GABA synthesis, in the dorsolateral prefrontal cortex of subjects with schizophrenia. However, little is known about the molecular regulation of lower cortical GAD67 levels in schizophrenia. The GAD67 promoter region contains a conserved Zif268 binding site and Zif268 activation is accompanied by increased GAD67 expression. Thus, altered expression of the immediate early gene Zif268 might contribute to lower levels of GAD67 mRNA in the dorsolateral prefrontal cortex of subjects with schizophrenia. We used polymerase chain reaction (qPCR) to quantify GAD67 and Zif268 mRNA levels in dorsolateral prefrontal cortex area 9 from 62 matched pairs of schizophrenia and healthy comparison subjects, and in situ hybridization to assess Zif268 expression at laminar and cellular levels of resolution. The effects of comorbid variables were assessed in human subjects and in antipsychotic-exposed monkeys. The specificity of the Zif268 findings was assessed by quantifying mRNA levels for other immediate early genes. GAD67 and Zif268 mRNA levels were significantly lower, and positively correlated, in subjects with schizophrenia. Zif268 expression was lower across cortical layers 206 (see Figure) and both Zif268 mRNA-positive neuron density and Zif268 mRNA levels per neuron were significantly lower in the subjects with schizophrenia. These findings were robust to the effects of the comorbid variables examined and differed from other immediate early genes. Deficient Zif268 mRNA expression may contribute to lower cortical GAD67 levels in schizophrenia, suggesting a potential mechanistic basis for altered cortical GABA synthesis and impaired cognition in schizophrenia.
|Kimoto S, Bazmi HH, Lewis DA: Lower expression of glutamic acid decarboxylase 67 in the prefrontal cortex of subjects with schizophrenia: Contribution of altered regulation by Zif268. Am J Psychiatry, ePub May 20, 2014.|