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

Abstract

Background: Impairments in certain cognitive processes (e.g., working memory) are typically most pronounced in schizophrenia (SZ), intermediate in bipolar disorder, and least in major depressive disorder. Given that working memory depends, in part, on neural circuitry that includes pyramidal cells in layer 3 (L3) and layer 5 (L5) of the dorsolateral prefrontal cortex (DLPFC), we sought to determine if transcriptome alterations in these neurons were shared or distinctive for each diagnosis.

Methods: Pools of L3 and L5 pyramidal cells in the DLPFC were individually captured by laser microdissection from 19 matched tetrads of unaffected comparison subjects and subjects with SZ, bipolar disorder, and major depressive disorder, and the messenger RNA was subjected to transcriptome profiling by microarray.

Results: In DLPFC L3 and L5 pyramidal cells, transcriptome alterations were numerous in subjects with SZ, but rare in subjects with bipolar disorder and major depressive disorder. The leading molecular pathways altered in subjects with SZ involved mitochondrial energy production and the regulation of protein translation. In addition, we did not find any significant transcriptome signatures related to psychosis or suicide.

Conclusions: In concert, these findings suggest that molecular alterations in DLPFC L3 and L5 pyramidal cells might be characteristic of the disease processes operative in individuals diagnosed with SZ and thus might contribute to the circuitry alterations underlying cognitive dysfunction in individuals with SZ.

Keywords: Bipolar disorder; Major depression; Microarray; Prefrontal cortex; Pyramidal neurons; Schizophrenia.

Figure 1

Heat maps representing all DEPs for SZ subjects in L3 PCs (A) and L5 PCs (B) compared to UC subjects. Heat maps were built using the expression values for each DEP in each subject after adjusting for covariate effects. Each row represents a probe set ordered by hierarchical clustering results; each column represents a subject ordered by tetrad number.