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Distinctive Transcriptome Alterations of Prefrontal Pyramidal Neurons in Schizophrenia and Schizoaffective Disorder
Arion D, Corradi JP, Tang S, Datta D, Boothe F, He A, Cacace AM, Zaczek R, Albright CF, Tseng G and Lewis DA
Molecular Psychiatry, Published Online

Individuals with schizophrenia experience cognitive problems, such as impaired working memory, in addition to the hallmark symptoms of psychosis. Working memory, the ability to keep a small amount of information in mind in order to guide thought or behavior, requires activity in a brain region called the dorsolateral prefrontal cortex (DLPFC). Working memory problems in people with schizophrenia are caused by the impaired activity of excitatory pyramidal neurons located in layers 3 and 5 of the DLPFC. Although many studies of schizophrenia have examined gene expression changes in DLPFC gray matter as a whole, the state of gene expression in the individual pyramidal cells located in these two layers remains largely unknown. 

Investigators in the Department of Psychiatry Translational Neuroscience Program, led by Drs. Dominique Arion and David Lewis, hypothesized that a specific examination of DLPFC layer 3 or 5 pyramidal cells would reveal new, and perhaps larger, schizophrenia-associated differences that could shed light on the mechanism of pyramidal cell dysfunction in the illness. Individual pyramidal cells in DLPFC layers 3 or 5 were removed by laser microdissection from a total 36 subjects with schizophrenia or schizoaffective disorder and 36 matched healthy comparison subjects. The mRNA from the cell collections was profiled by microarray, and abnormal gene expression was validated with quantitative PCR. 

Expression of genes involved in two key cellular processes - energy production in mitochondria and waste degradation in the ubiquitin?proteasome system - was markedly changed in patients compared to controls, with the majority of gene changes reflecting lower mRNA levels in the schizophrenia group. The mitochondrial-related mRNA changes were more prominent in layer 3 pyramidal cells, while the altered expression of genes involved in the ubiquitin-proteasome system was more prominent in pyramidal cells from layer 5. Consistent with the investigators? hypothesis, many of these alterations were either not present or found to a lesser degree in samples of total DLPFC gray matter from the same subjects. Strikingly, Arion and colleagues also found that the majority of these schizophrenia-associated gene changes were not present in the subjects with schizoaffective disorder. 

These new findings reveal layer 3 and layer 5 pyramidal cell-specific expression deficits in genes involved in the mitochondrial and ubiquitin-proteasome systems in the DLPFC of subjects with schizophrenia. The absence of similar alterations in schizoaffective subjects is consistent with the observation that people with schizophrenia have greater impairments in working memory than those with schizoaffective disorder. Thus, the changes in pyramidal cell gene expression may underlie the more severe cognitive impairments in schizophrenia subjects, and provide a molecular-cellular basis for differences in the cognitive phenotypes of these two disorders.

Contributors:
Dominique Arion, PhD and David A. Lewis, MD (Department of Psychiatry, University of Pittsburgh)

John P. Corradi, PhD, Aiqing He, PhD, Angela M. Cacace, PhD, Robert Zaczek, PhD and Charles F. Albright, PhD (Bristol-Myers Squibb, USA)

Shaowu Tang, PhD and George Tseng, ScD (Department of Biostatistics, University of Pittsburgh)

Dibyadeep Datta, BA and Franklyn Boothe, BS (Department of Neuroscience, University of Pittsburgh)

This article appeared in Molecular Psychiatry.  Click here to view the abstract.