Transcriptome Alterations of Prefrontal Cortical Parvalbumin Neurons in Schizophrenia

Schizophrenia is associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). This dysfunction is manifest as cognitive deficits that appear to arise from disturbances in gamma frequency oscillations. These oscillations are generated in DLPFC layer 3 via reciprocal connections between pyramidal cells and parvalbumin (PV)-containing interneurons. The density of cortical PV neurons is not altered in schizophrenia, but expression levels of several transcripts involved in PV cell function, including PV, are lower in the disease. However, the transcriptome of PV cells has not been comprehensively assessed in a large cohort of subjects with schizophrenia. In this study, we combined an immunohistochemical approach, laser microdissection, and microarray profiling to analyze the transcriptome of DLPFC layer 3 PV cells in 36 matched pairs of schizophrenia and unaffected comparison subjects. Over 800 transcripts in PV neurons were identified as differentially-expressed in schizophrenia subjects; most of these alterations have not previously been reported. The altered transcripts were enriched for pathways involved in mitochondrial function and tight junction signaling. Comparison with the transcriptome of layer 3 pyramidal cells from the same subjects revealed both shared and distinct disease-related effects on gene expression between cell types. Furthermore, network structures of gene pathways differed across cell types and subject groups. For example, as shown in the figure, the mean degree of connectivity of the differentially expressed genes (DEGs) (xs) were compared with randomly generated networks (ovals) across cell types and diagnoses (C, unaffected comparison; SZ, schizophrenia). Any network plotted above the whiskers in the box plots is significantly connected (P<0.001). These findings provide new insights into cell type-specific molecular alterations in schizophrenia which may point toward novel strategies for identifying therapeutic targets.
Transcriptome Alterations of Prefrontal Cortical Parvalbumin Neurons in Schizophrenia. Enwright III JF, Huo Z, Arion D, Corradi JP, Tseng G, Lewis DA. Mol Psychiatry. 2017 Nov 7. doi: 10.1038/mp.2017.216. [Epub ahead of print] PMID: 29112193.

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David A. Lewis, M.D. | Department of Psychiatry | University of Pittsburgh
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