title: Altered Markers of Cortical γ-Aminobutyric Acid Neuronal Activity in Schizophrenia: Role of the NARP Gene.
abstract: OBJECTIVE
  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.
  
  
  OBJECTIVE
  To quantify in individuals with schizophrenia the expression of immediate early genes (NARP, ARC, and SGK1) regulating glutamate synaptic neurotransmission.
  
  
  METHODS
  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. This study was conducted between January 1, 2013, and November 30, 2014.
  
  
  METHODS
  Expression levels for NARP, ARC, and SGK1 messenger RNA (mRNA) were compared between specimens from individuals with schizophrenia and controls. Diagnostic specificity was assessed by quantifying NARP mRNA levels in specimens from individuals with mood disorders.
  
  
  RESULTS
  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 (mean [SD], 0.036 [0.018] vs 0.049 [0.015]; F1,114 = 21.0; P < .001). Levels of ARC (F1,112 = 0.93; P = .34) and SGK1 (F1,110 = 2.52; P = .12) were not significant. These findings were supported by in situ hybridization (NARP; individuals with schizophrenia vs controls: 40.1% lower [P = .003]) and microarray analyses (NARP; individuals with schizophrenia vs controls: 12.2% lower in layer 3 [P = .11] and 14.6% lower in layer 5 pyramidal cells [P = .001]). 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 (-18.2%; F1,60 = 11.39; P = .001) and major depressive disorder (-21.7%; F1,30 = 5.36; P = .03) specimens, especially those from individuals with psychosis. In all 3 diagnostic groups, NARP mRNA levels were positively correlated (all r ≥ 0.53; all P ≤ .02) with somatostatin mRNA, the expression of which is activity dependent.
  
  
  CONCLUSIONS
  Given the role of NARP in the formation of excitatory inputs to parvalbumin (and perhaps somatostatin) interneurons, our 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.
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania2Department of Psychiatry, Nara Medical University, Nara, Japan.
authors.forename: Sohei
authors.initials: S
authors.lastname: Kimoto
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania3Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Zaki
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: H Holly
authors.initials: HH
authors.lastname: Bazmi
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania3Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: David A
authors.initials: DA
authors.lastname: Lewis
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D001714:Bipolar Disorder / Q000378:metabolism; D002097:C-Reactive Protein / Q000096:biosynthesis*; D016022:Case-Control Studies; D003598:Cytoskeletal Proteins / Q000096:biosynthesis; D003865:Major Depressive Disorder / Q000378:metabolism; D005260:Female; D005968:Glutamate Decarboxylase / Q000096:biosynthesis; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009474:Neurons / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D012559:Schizophrenia / Q000378:metabolism*; D013004:Somatostatin / Q000096:biosynthesis; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases; D000099153:Pentraxins
chemical_list: D015415:Biomarkers; D002097:C-Reactive Protein; D003598:Cytoskeletal Proteins; D005968:Glutamate Decarboxylase; D017874:Immediate-Early Proteins; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D013004:Somatostatin; D005680:gamma-Aminobutyric Acid; D000099184:Serum-Glucocorticoid Regulated Kinases; D000099153:Pentraxins; C092069:activity regulated cytoskeletal-associated protein; C402565:glutamate decarboxylase 1