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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, Lewis DA - Mol. Psychiatry (2015)

Bottom Line: We hypothesized that interrogating gene expression, specifically in DLPFC layer 3 or 5 pyramidal cells, would reveal new and/or more robust schizophrenia-associated differences that would provide new insights into the nature of pyramidal cell dysfunction in the illness.Many of these alterations were not present, or found to a lesser degree, in samples of DLPFC gray matter from the same subjects, suggesting that they are pyramidal cell specific.These cell type-specific transcriptome signatures are not characteristic of schizoaffective disorder, providing a potential molecular-cellular basis of differences in clinical phenotypes.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

ABSTRACT
Schizophrenia is associated with alterations in working memory that reflect dysfunction of dorsolateral prefrontal cortex (DLPFC) circuitry. Working memory depends on the activity of excitatory pyramidal cells in DLPFC layer 3 and, to a lesser extent, in layer 5. Although many studies have profiled gene expression in DLPFC gray matter in schizophrenia, little is known about cell-type-specific transcript expression in these two populations of pyramidal cells. We hypothesized that interrogating gene expression, specifically in DLPFC layer 3 or 5 pyramidal cells, would reveal new and/or more robust schizophrenia-associated differences that would provide new insights into the nature of pyramidal cell dysfunction in the illness. We also sought to determine the impact of other variables, such as a diagnosis of schizoaffective disorder or medication use at the time of death, on the patterns of gene expression in pyramidal neurons. Individual pyramidal cells in DLPFC layers 3 or 5 were captured by laser microdissection from 36 subjects with schizophrenia or schizoaffective disorder and matched normal comparison subjects. The mRNA from cell collections was subjected to transcriptome profiling by microarray followed by quantitative PCR validation. Expression of genes involved in mitochondrial (MT) or ubiquitin-proteasome system (UPS) functions were markedly downregulated in the patient group (P-values for MT-related and UPS-related pathways were <10(-7) and <10(-5), respectively). MT-related gene alterations were more prominent in layer 3 pyramidal cells, whereas UPS-related gene alterations were more prominent in layer 5 pyramidal cells. Many of these alterations were not present, or found to a lesser degree, in samples of DLPFC gray matter from the same subjects, suggesting that they are pyramidal cell specific. Furthermore, these findings principally reflected alterations in the schizophrenia subjects were not present or present to a lesser degree in the schizoaffective disorder subjects (diagnosis of schizoaffective disorder was the most significant covariate, P<10(-6)) and were not attributable to factors frequently comorbid with schizophrenia. In summary, our findings reveal expression deficits in MT- and UPS-related genes specific to layer 3 and/or layer 5 pyramidal cells in the DLPFC of schizophrenia subjects. These cell type-specific transcriptome signatures are not characteristic of schizoaffective disorder, providing a potential molecular-cellular basis of differences in clinical phenotypes.

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Comparison of the main effect of disease relative to the covariate of schizoaffective disorder(A) The effect of disease relative to the effect of the covariate of schizoaffective disorder is shown for each of the 1,000 permutations where a significant effect of schizoaffective disorder was detected in both layers 3 and 5. Due to the filters used for detection of DEPs, there are no data points around a disease effect equal to zero. Note that the main effect of disease and effect of schizoaffective disorder are in the opposite directions in both layers. (B) Heat map illustrating the transcripts that were differentially expressed in pyramidal neurons between subjects with schizophrenia (SZ) and subjects with schizoaffective disorder (SAD) for each layer. Due to the high number of DEPs, only transcripts with a minimum log 2 transformed expression level ≥5 are shown for each layer. In addition, for layer 5 only DEPs with a disease effect greater than +/−0.7 are shown. (C) Log 2 transformed transcript expression levels for UQCRFS1 in layer 3 and UBL5 in layer 5 for comparison (CR), schizophrenia (SZ) and schizoaffective disorder (SAD) subjects. For each transcript, groups not sharing the same letter are significantly different by Tukey post-hoc analysis.
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Figure 2: Comparison of the main effect of disease relative to the covariate of schizoaffective disorder(A) The effect of disease relative to the effect of the covariate of schizoaffective disorder is shown for each of the 1,000 permutations where a significant effect of schizoaffective disorder was detected in both layers 3 and 5. Due to the filters used for detection of DEPs, there are no data points around a disease effect equal to zero. Note that the main effect of disease and effect of schizoaffective disorder are in the opposite directions in both layers. (B) Heat map illustrating the transcripts that were differentially expressed in pyramidal neurons between subjects with schizophrenia (SZ) and subjects with schizoaffective disorder (SAD) for each layer. Due to the high number of DEPs, only transcripts with a minimum log 2 transformed expression level ≥5 are shown for each layer. In addition, for layer 5 only DEPs with a disease effect greater than +/−0.7 are shown. (C) Log 2 transformed transcript expression levels for UQCRFS1 in layer 3 and UBL5 in layer 5 for comparison (CR), schizophrenia (SZ) and schizoaffective disorder (SAD) subjects. For each transcript, groups not sharing the same letter are significantly different by Tukey post-hoc analysis.

Mentions: For all 4 MT pathways, the q values were smaller for layer 3 compared to layer 5. Conversely, for all 8 UPS pathways the q values were significant only in layer 5 (Figure 2A). These differences suggest laminar-specificity in altered pyramidal cell gene expression in schizophrenia, with MT-related alterations more robust in layer 3 and UPS-related alterations restricted to layer 5.


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, Lewis DA - Mol. Psychiatry (2015)

Comparison of the main effect of disease relative to the covariate of schizoaffective disorder(A) The effect of disease relative to the effect of the covariate of schizoaffective disorder is shown for each of the 1,000 permutations where a significant effect of schizoaffective disorder was detected in both layers 3 and 5. Due to the filters used for detection of DEPs, there are no data points around a disease effect equal to zero. Note that the main effect of disease and effect of schizoaffective disorder are in the opposite directions in both layers. (B) Heat map illustrating the transcripts that were differentially expressed in pyramidal neurons between subjects with schizophrenia (SZ) and subjects with schizoaffective disorder (SAD) for each layer. Due to the high number of DEPs, only transcripts with a minimum log 2 transformed expression level ≥5 are shown for each layer. In addition, for layer 5 only DEPs with a disease effect greater than +/−0.7 are shown. (C) Log 2 transformed transcript expression levels for UQCRFS1 in layer 3 and UBL5 in layer 5 for comparison (CR), schizophrenia (SZ) and schizoaffective disorder (SAD) subjects. For each transcript, groups not sharing the same letter are significantly different by Tukey post-hoc analysis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492919&req=5

Figure 2: Comparison of the main effect of disease relative to the covariate of schizoaffective disorder(A) The effect of disease relative to the effect of the covariate of schizoaffective disorder is shown for each of the 1,000 permutations where a significant effect of schizoaffective disorder was detected in both layers 3 and 5. Due to the filters used for detection of DEPs, there are no data points around a disease effect equal to zero. Note that the main effect of disease and effect of schizoaffective disorder are in the opposite directions in both layers. (B) Heat map illustrating the transcripts that were differentially expressed in pyramidal neurons between subjects with schizophrenia (SZ) and subjects with schizoaffective disorder (SAD) for each layer. Due to the high number of DEPs, only transcripts with a minimum log 2 transformed expression level ≥5 are shown for each layer. In addition, for layer 5 only DEPs with a disease effect greater than +/−0.7 are shown. (C) Log 2 transformed transcript expression levels for UQCRFS1 in layer 3 and UBL5 in layer 5 for comparison (CR), schizophrenia (SZ) and schizoaffective disorder (SAD) subjects. For each transcript, groups not sharing the same letter are significantly different by Tukey post-hoc analysis.
Mentions: For all 4 MT pathways, the q values were smaller for layer 3 compared to layer 5. Conversely, for all 8 UPS pathways the q values were significant only in layer 5 (Figure 2A). These differences suggest laminar-specificity in altered pyramidal cell gene expression in schizophrenia, with MT-related alterations more robust in layer 3 and UPS-related alterations restricted to layer 5.

Bottom Line: We hypothesized that interrogating gene expression, specifically in DLPFC layer 3 or 5 pyramidal cells, would reveal new and/or more robust schizophrenia-associated differences that would provide new insights into the nature of pyramidal cell dysfunction in the illness.Many of these alterations were not present, or found to a lesser degree, in samples of DLPFC gray matter from the same subjects, suggesting that they are pyramidal cell specific.These cell type-specific transcriptome signatures are not characteristic of schizoaffective disorder, providing a potential molecular-cellular basis of differences in clinical phenotypes.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

ABSTRACT
Schizophrenia is associated with alterations in working memory that reflect dysfunction of dorsolateral prefrontal cortex (DLPFC) circuitry. Working memory depends on the activity of excitatory pyramidal cells in DLPFC layer 3 and, to a lesser extent, in layer 5. Although many studies have profiled gene expression in DLPFC gray matter in schizophrenia, little is known about cell-type-specific transcript expression in these two populations of pyramidal cells. We hypothesized that interrogating gene expression, specifically in DLPFC layer 3 or 5 pyramidal cells, would reveal new and/or more robust schizophrenia-associated differences that would provide new insights into the nature of pyramidal cell dysfunction in the illness. We also sought to determine the impact of other variables, such as a diagnosis of schizoaffective disorder or medication use at the time of death, on the patterns of gene expression in pyramidal neurons. Individual pyramidal cells in DLPFC layers 3 or 5 were captured by laser microdissection from 36 subjects with schizophrenia or schizoaffective disorder and matched normal comparison subjects. The mRNA from cell collections was subjected to transcriptome profiling by microarray followed by quantitative PCR validation. Expression of genes involved in mitochondrial (MT) or ubiquitin-proteasome system (UPS) functions were markedly downregulated in the patient group (P-values for MT-related and UPS-related pathways were <10(-7) and <10(-5), respectively). MT-related gene alterations were more prominent in layer 3 pyramidal cells, whereas UPS-related gene alterations were more prominent in layer 5 pyramidal cells. Many of these alterations were not present, or found to a lesser degree, in samples of DLPFC gray matter from the same subjects, suggesting that they are pyramidal cell specific. Furthermore, these findings principally reflected alterations in the schizophrenia subjects were not present or present to a lesser degree in the schizoaffective disorder subjects (diagnosis of schizoaffective disorder was the most significant covariate, P<10(-6)) and were not attributable to factors frequently comorbid with schizophrenia. In summary, our findings reveal expression deficits in MT- and UPS-related genes specific to layer 3 and/or layer 5 pyramidal cells in the DLPFC of schizophrenia subjects. These cell type-specific transcriptome signatures are not characteristic of schizoaffective disorder, providing a potential molecular-cellular basis of differences in clinical phenotypes.

Show MeSH
Related in: MedlinePlus