Hot Publication - Kimoto et al.

Lower expression of glutamic acid decarboxylase 67 in the prefrontal cortex of subjects with schizophrenia: Contribution of altered regulation by Zif268
Kimoto S, Bazmi HH, Lewis DA 
American Journal of Psychiatry doi:10.1176/appi.ajp.2014.14010004

The cognitive deficits of schizophrenia are thought to be at least partially due to lower levels of the enzyme GAD67, a key player in the synthesis of the inhibitory neurotransmitter GABA. In patients with schizophrenia, lower levels of GAD67 are present in the dorsolateral prefrontal cortex (DLPFC), a brain area known to be critical for cognition. The root cause of the GAD67 deficit is currently unknown, prompting a team of Translational Neuroscience Program researchers to investigate possible sources of impaired GABA synthesis in the DLPFC.

The expression of GAD67 is dependent on neuronal activity. One potential regulator of GAD67 is the transcription factor Zif268, which is also transiently expressed in response to neuronal activity. Prior studies have demonstrated that the activation of Zif268 increases GAD67 levels, so Dr. Sohei Kimoto, Ms. Holly Bazmi, and Dr. David Lewis reasoned that a disruption of Zif268 expression could result in the lower levels of GAD67 observed in schizophrenia.

The researchers quantified the amount of GAD67 and Zif268 mRNA in the dorsolateral prefrontal cortex of 62 pairs of subjects with schizophrenia and matched comparison subjects. Dr. Kimoto and colleagues found that the levels of both GAD67 and Zif268 mRNA were lower in the schizophrenia subjects. In addition, the levels of GAD67 and Zif268 were positively correlated in the schizophrenia subjects. These data suggest that lower levels of Zif268 may mediate the reduction in DLPFC GAD67 levels, and in turn contribute to the cognitive deficits associated with schizophrenia.

Contributors:  
Sohei Kimoto, MD, PhD; H. Holly Bazmi, MS; David A. Lewis, MD (Departments of Psychiatry and Neuroscience, University of Pittsburgh)

The results of this study were published in The American Journal of Psychiatry.  Click here for a link to the abstract.