Altered Markers of Cortical γ-Aminobutyric Acid Neuronal Activity in Schizophrenia

Abstract

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. DESIGN, SETTING, AND PARTICIPANTS 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. MAIN OUTCOMES AND MEASURESExpression 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]; F 1,114 = 21.0; P < .001). Levels of ARC (F 1,112 = 0.93; P = .34) and SGK1 (F 1,110 = 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%; F 1,60 = 11.39; P = .001) and major depressive disorder (−21.7%; F 1,30 = 5.36; P = .03) specimens, especially those from individuals with psychosis. In all 3 diagnostic groups, NARP mRNA levels were positively correlated (all r Ն 0.53; all P Յ .02) with somatostatin mRNA, the expression of which is activity dependent. CONCLUSIONS AND RELEVANCEGiven 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 excitator...

Pathological Basis for Deficient Excitatory Drive to Cortical Parvalbumin Interneurons in Schizophrenia

“…For example, the ErbB4 signaling pathway induces the formation of excitatory synapses on PV interneurons(11, 43, 44) and the release of neuronal pentraxin 2 (Narp) from pyramidal cells recruits excitatory synapses selectively on PV interneurons in an activity-dependent manner(28). Both an abnormal shift in ErbB4 splicing at the JM locus(45, 46) and lower Narp transcript levels have been shown in the DLPFC of subjects with schizophrenia, including those included in the present study(21, 47). Across these subjects, the density of VGlut1+/PSD95+ puncta on PV+ cell bodies was significantly correlated with the ratio of ErbB4 JM-a to JM-b splice variants in cortical layer 4 (R=-0.436, p=0.005) and with Narp mRNA levels in total gray matter (R=0.351, p=0.026).…”

Transcriptome Alterations in Prefrontal Pyramidal Cells Distinguish Schizophrenia From Bipolar and Major Depressive Disorders

“…Furthermore, at least some psychotic features are thought to emerge from cognitive disturbances that are shared, albeit to different degrees, across all three diagnoses (3-5, 37). The idea that psychosis might have a conserved molecular substrate across diagnoses is supported by previous reports of certain transcripts that were altered in SZ and psychotic BP subjects but not BP subjects without psychosis (38), or that were altered in SZ and showed more pronounced alterations in mood disorder subjects with, than without, psychotic features (39). However, here we did not find any significant mRNA expression alterations in L3 or L5 PCs in subjects with psychosis after controlling for effects of diagnosis.…”

Frontal Glutamate and γ-Aminobutyric Acid Levels and Their Associations With Mismatch Negativity and Digit Sequencing Task Performance in Schizophrenia

“…Impaired working memory is a key cognitive deficit in schizophrenia. 60 γ-Aminobutyric acid dysfunction is the primary underlying neurochemical mechanism used to explain the working memory deficit 61-63 based on reduced expression of GABA enzyme glutamic acid decarboxylase 67 (GAD 67 ) in postmortem brain, 61,62 genetic evidence linking GAD 67 to working memory, 64 and GABAergic drug challenges that manipulate working memory. 65 In this context, identifying a link between lower endogenous GABA and impaired working memory provides support to this theory.…”