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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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Top 12 gene pathways based on most significant q values altered in pyramidal cells in subjects with schizophrenia(A) Twelve most significantly altered gene pathways, based on smallest q values across both layers 3 and 5. Note that MT-related pathways show smaller p values in layer 3 (L3) than layer 5 (L5) pyramidal cells and that UPS-related pathways are not altered in layer 3 pyramidal cells. NS, non-significant. (B) Venn diagram illustrating the overlap in genes among the four most altered MT-related pathways in schizophrenia; (C) Venn diagram illustrating the overlap in genes among the eight most altered UPS-related pathways in schizophrenia.
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Figure 1: Top 12 gene pathways based on most significant q values altered in pyramidal cells in subjects with schizophrenia(A) Twelve most significantly altered gene pathways, based on smallest q values across both layers 3 and 5. Note that MT-related pathways show smaller p values in layer 3 (L3) than layer 5 (L5) pyramidal cells and that UPS-related pathways are not altered in layer 3 pyramidal cells. NS, non-significant. (B) Venn diagram illustrating the overlap in genes among the four most altered MT-related pathways in schizophrenia; (C) Venn diagram illustrating the overlap in genes among the eight most altered UPS-related pathways in schizophrenia.

Mentions: The 1,783 DEPs detected by microarray correspond to 1,420 genes. After selecting pathways containing >10 and <200 genes and using a false discovery rate of 5%, these 1,420 differentially expressed genes were enriched in 68 biological pathways. Of the top 12 affected pathways as ranked by q values (Figure 1A), four were related to mitochondrial (MT) function and eight to ubiquitin proteasome system (UPS) function. The high level of overlap among the DEPs belonging to the MT- or the UPS-related pathways is shown in Figures 1B and 1C, respectively. Furthermore, the three most altered pathways involve MT functions, and of the 40 DETs with the most significant differences (all q<10−17; Table 2) between the subject groups, 11 were related to MT function. All of these transcripts were down-regulated in schizophrenia subjects.


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)

Top 12 gene pathways based on most significant q values altered in pyramidal cells in subjects with schizophrenia(A) Twelve most significantly altered gene pathways, based on smallest q values across both layers 3 and 5. Note that MT-related pathways show smaller p values in layer 3 (L3) than layer 5 (L5) pyramidal cells and that UPS-related pathways are not altered in layer 3 pyramidal cells. NS, non-significant. (B) Venn diagram illustrating the overlap in genes among the four most altered MT-related pathways in schizophrenia; (C) Venn diagram illustrating the overlap in genes among the eight most altered UPS-related pathways in schizophrenia.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Top 12 gene pathways based on most significant q values altered in pyramidal cells in subjects with schizophrenia(A) Twelve most significantly altered gene pathways, based on smallest q values across both layers 3 and 5. Note that MT-related pathways show smaller p values in layer 3 (L3) than layer 5 (L5) pyramidal cells and that UPS-related pathways are not altered in layer 3 pyramidal cells. NS, non-significant. (B) Venn diagram illustrating the overlap in genes among the four most altered MT-related pathways in schizophrenia; (C) Venn diagram illustrating the overlap in genes among the eight most altered UPS-related pathways in schizophrenia.
Mentions: The 1,783 DEPs detected by microarray correspond to 1,420 genes. After selecting pathways containing >10 and <200 genes and using a false discovery rate of 5%, these 1,420 differentially expressed genes were enriched in 68 biological pathways. Of the top 12 affected pathways as ranked by q values (Figure 1A), four were related to mitochondrial (MT) function and eight to ubiquitin proteasome system (UPS) function. The high level of overlap among the DEPs belonging to the MT- or the UPS-related pathways is shown in Figures 1B and 1C, respectively. Furthermore, the three most altered pathways involve MT functions, and of the 40 DETs with the most significant differences (all q<10−17; Table 2) between the subject groups, 11 were related to MT function. All of these transcripts were down-regulated in schizophrenia subjects.

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