Polymerase Chain Reaction Determination of Relative Messenger RNA (mRNA) Levels for NARP, ARC, and SGK1 in Schizophrenia and Healthy Control Samples
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 interneurons. Thus, gamma oscillations depend, in part, on the number of synaptic glutamate receptors on parvalbumin interneurons. However, little is known about the molecular factors that regulate glutamate receptor-mediated excitation of parvalbumin interneurons in schizophrenia. This study sought to quantify in individuals with schizophrenia the expression of immediate early genes (NARP, ARC, and SGK1) regulating glutamate synaptic neurotransmission. Postmortem brain specimens (n=206) were obtained from individuals with schizophrenia, bipolar disorder, or major depressive disorder and from well-matched healthy persons (controls). For a study of brain tissue, 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 by 25.6% in specimens from individuals with schizophrenia compared with the controls (Figure, panel B), whereas levels of ARC and SGK1 mRNAs did not differ. Lower NARP levels were confirmed by in situ hybridization and by microarray analyses in layer 3 and in layer 5 pyramidal cells. In schizophrenia specimens, NARP mRNA levels were positively correlated with GAD67 mRNA (r=0.55; P‹.001); the expression of GAD67 mRNA in parvalbumin interneurons is activity dependent. The NARP mRNA levels were also lower than healthy controls in bipolar disorder and major depressive disorder subjects, especially those from individuals with psychosis. In all 3 diagnostic groups, NARP mRNA levels were positively correlated (all r≥0.53; all P≤0.02) 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) interneurons (Figure, panel A), these findings 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 γ-aminobutyric acid in these interneurons, contributing to a reduced capacity to generate the gamma oscillations required for working memory.
|Sohei Kimoto, MD, PhD, Mark M. Zaki, H. Holly Bazmi, MS, David A. Lewis, MD. Polymerase Chain Reaction Determination of Relative Messenger RNA (mRNA) Levels for NARP, ARC, and SGK1 in Schizophrenia and Healthy Control Samples, JAMA Psychiatry. 2015;72(8):747-756.|