Enwright et al. Offer New Insights into Cell Type-Specific Molecular Alterations in Schizophrenia

Published in Molecular Psychiatry

Department of Psychiatry members John Enwright, PhD; Dominique Arion, PhD; and David A. Lewis, MD, along with colleagues from other departments, have identified cell type-specific molecular alterations in schizophrenia, which could propel strategies for identifying novel therapeutic targets. The researchers investigated the molecular alterations associated with schizophrenia at the level of specific cell types, showing distinct disease-related effects on gene expression in Layer 3 (L3) parvalbumin (PV) cells, as well as transcriptome alterations that are shared with L3 pyramidal cells (PCs). Comparison of the findings across cell types provides additional evidence, suggesting that many of the alterations in PV cells could be secondary to events in the L3 PCs that innervate them. 

In schizophrenia, alterations in the dorsolateral prefrontal cortex (DLPFC) are thought to underlie certain cognitive deficits, including working memory impairments, associated with the disease. Almost all transcriptome-wide studies have been conducted in total grey matter homogenates, likely masking cell-type specific alterations due to cellular heterogeneity. In this study, researchers combined an immunohistochemical approach, laser microdissection, and microarray profiling to analyze the transcriptome of DLPFC L3 PV cells in 36 matched pairs of schizophrenia and unaffected comparison subjects. They identified more than 800 transcripts in PV neurons as differentially expressed in subjects with schizophrenia. When they compared the transcriptome of L3 PCs from the same subjects, they found 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.

These findings provide new insights into cell type-specific molecular alterations in schizophrenia and may point toward novel therapeutic targets.

Transcriptome Alterations of Prefrontal Cortical Parvalbumin Neurons in Schizophrenia
Enwright III JF, Huo Z, Arion D, Corradi JP, Tseng G, Lewis DA
Molecular Psychiatry, Published online November 7, 2017. doi:10.1001/jamapsychiatry.2017.1763