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Altered Markers of Cortical ?-Aminobutyric Acid Neuronal Activity in Schizophrenia:   Role of the NARP Gene 
Kimoto S, Zaki MM, Bazmi HH and Lewis DA
JAMA Psychiatry, 72:747-756, 2015

In schizophrenia, working memory deficits appear to reflect abnormalities in the generation of gamma oscillations in the dorsolateral prefrontal cortex. The generation of gamma oscillations requires the phasic excitation of inhibitory parvalbumin-containing neurons. Thus, gamma oscillations depend, in part, on the number of synaptic glutamate receptors on parvalbumin neurons. However, little is known about the molecular factors that regulate glutamate receptor?mediated excitation of parvalbumin neurons in schizophrenia.   Investigators in the Department?s Translational Neuroscience Program conducted a study to quantify in individuals with schizophrenia the expression of immediate early genes (NARP, ARC, and SGK1) regulating glutamate synaptic neurotransmission. 

Led by Dr. Sohei Kimoto and senior author Dr. David Lewis, the researchers examined postmortem brain samples containing the dorsolateral prefrontal cortex from 206 individuals with schizophrenia, bipolar disorder or major depressive disorder and well-matched healthy persons.  Quantitative polymerase chain reaction, in situ hybridization, or microarray analyses were used to measure transcript levels in the dorsolateral prefrontal cortex at gray matter, laminar, and cellular levels of resolutions.   By quantitative polymerase chain reaction, levels of NARP mRNA were significantly lower  in  individuals with schizophrenia compared with healthy individuals.   Levels of ARC and SGK1 mRNAs did not differ between groups. These findings were supported by in situ hybridization and by microarray analyses of pyramidal cells in layers 3 and 5s. In schizophrenia, NARP mRNA levels were positively correlated with GAD67 mRNA whose  expression nin parvalbumin neurons is activity dependent. The NARP mRNA levels were also lower than healthy individuals in bipolar disorder and major depressive disorder specimens, especially those individuals with psychosis. In all three diagnostic groups, NARP mRNA levels were positively correlated with somatostatin mRNA, the expression of which is activity dependent. 

Given the role of NARP in the formation of excitatory inputs to parvalbumin (and perhaps somatostatin) neurons, findings from this study suggest that lower NARP mRNA expression contributes to lower excitatory drive onto parvalbumin interneurons in schizophrenia. This reduced excitatory drive may lead to lower synthesis of ?-aminobutyric acid in these neurons, contributing to a reduced capacity to generate the gamma oscillations required for working memory. 

Contributors:
Sohei Kimoto, MD, PhD (Department of Psychiatry, University of Pittsburgh and Nara Medical University, Nara, Japan)

David A. Lewis, MD, Mark M. Zaki, and H. Holly Bazmi, MS (Department of Psychiatry, University of Pittsburgh)

This article appears in the journal JAMA Psychiatry.  Click here to view the abstract.