Transcriptome alterations are enriched for synapse-associated genes in the striatum of subjects with obsessive-compulsive disorder
Abstract Obsessive-compulsive disorder (OCD) is a chronic and severe psychiatric disorder for which effective treatment options are limited. Structural and functional neuroimaging studies have consistently implicated the orbitofrontal cortex (OFC) and striatum in the pathophysiology of the disorder....
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-03-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-021-01290-1 |
| _version_ | 1819119970348433408 |
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| author | Sean C. Piantadosi Lora L. McClain Lambertus Klei Jiebiao Wang Brittany L. Chamberlain Sara A. Springer David A. Lewis Bernie Devlin Susanne E. Ahmari |
| author_facet | Sean C. Piantadosi Lora L. McClain Lambertus Klei Jiebiao Wang Brittany L. Chamberlain Sara A. Springer David A. Lewis Bernie Devlin Susanne E. Ahmari |
| author_sort | Sean C. Piantadosi |
| collection | DOAJ |
| description | Abstract Obsessive-compulsive disorder (OCD) is a chronic and severe psychiatric disorder for which effective treatment options are limited. Structural and functional neuroimaging studies have consistently implicated the orbitofrontal cortex (OFC) and striatum in the pathophysiology of the disorder. Recent genetic evidence points to involvement of components of the excitatory synapse in the etiology of OCD. However, the transcriptional alterations that could link genetic risk to known structural and functional abnormalities remain mostly unknown. To assess potential transcriptional changes in the OFC and two striatal regions (caudate nucleus and nucleus accumbens) of OCD subjects relative to unaffected comparison subjects, we sequenced messenger RNA transcripts from these brain regions. In a joint analysis of all three regions, 904 transcripts were differentially expressed between 7 OCD versus 8 unaffected comparison subjects. Region-specific analyses highlighted a smaller number of differences, which concentrated in caudate and nucleus accumbens. Pathway analyses of the 904 differentially expressed transcripts showed enrichment for genes involved in synaptic signaling, with these synapse-associated genes displaying lower expression in OCD subjects relative to unaffected comparison subjects. Finally, we estimated that cell type fractions of medium spiny neurons were lower whereas vascular cells and astrocyte fractions were higher in tissue of OCD subjects. Together, these data provide the first unbiased examination of differentially expressed transcripts in both OFC and striatum of OCD subjects. These transcripts encoded synaptic proteins more often than expected by chance, and thus implicate the synapse as a vulnerable molecular compartment for OCD. |
| first_indexed | 2024-12-22T06:13:14Z |
| format | Article |
| id | doaj.art-eef094f7d50846a8bcecfcb3bb973610 |
| institution | Directory Open Access Journal |
| issn | 2158-3188 |
| language | English |
| last_indexed | 2024-12-22T06:13:14Z |
| publishDate | 2021-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj.art-eef094f7d50846a8bcecfcb3bb9736102022-12-21T18:36:10ZengNature Publishing GroupTranslational Psychiatry2158-31882021-03-0111111110.1038/s41398-021-01290-1Transcriptome alterations are enriched for synapse-associated genes in the striatum of subjects with obsessive-compulsive disorderSean C. Piantadosi0Lora L. McClain1Lambertus Klei2Jiebiao Wang3Brittany L. Chamberlain4Sara A. Springer5David A. Lewis6Bernie Devlin7Susanne E. Ahmari8Center for Neuroscience, University of PittsburghDepartment of Psychiatry, University of PittsburghDepartment of Psychiatry, University of PittsburghDepartment of Biostatistics, University of PittsburghCenter for Neuroscience, University of PittsburghCenter for Neuroscience, University of PittsburghCenter for Neuroscience, University of PittsburghDepartment of Psychiatry, University of PittsburghCenter for Neuroscience, University of PittsburghAbstract Obsessive-compulsive disorder (OCD) is a chronic and severe psychiatric disorder for which effective treatment options are limited. Structural and functional neuroimaging studies have consistently implicated the orbitofrontal cortex (OFC) and striatum in the pathophysiology of the disorder. Recent genetic evidence points to involvement of components of the excitatory synapse in the etiology of OCD. However, the transcriptional alterations that could link genetic risk to known structural and functional abnormalities remain mostly unknown. To assess potential transcriptional changes in the OFC and two striatal regions (caudate nucleus and nucleus accumbens) of OCD subjects relative to unaffected comparison subjects, we sequenced messenger RNA transcripts from these brain regions. In a joint analysis of all three regions, 904 transcripts were differentially expressed between 7 OCD versus 8 unaffected comparison subjects. Region-specific analyses highlighted a smaller number of differences, which concentrated in caudate and nucleus accumbens. Pathway analyses of the 904 differentially expressed transcripts showed enrichment for genes involved in synaptic signaling, with these synapse-associated genes displaying lower expression in OCD subjects relative to unaffected comparison subjects. Finally, we estimated that cell type fractions of medium spiny neurons were lower whereas vascular cells and astrocyte fractions were higher in tissue of OCD subjects. Together, these data provide the first unbiased examination of differentially expressed transcripts in both OFC and striatum of OCD subjects. These transcripts encoded synaptic proteins more often than expected by chance, and thus implicate the synapse as a vulnerable molecular compartment for OCD.https://doi.org/10.1038/s41398-021-01290-1 |
| spellingShingle | Sean C. Piantadosi Lora L. McClain Lambertus Klei Jiebiao Wang Brittany L. Chamberlain Sara A. Springer David A. Lewis Bernie Devlin Susanne E. Ahmari Transcriptome alterations are enriched for synapse-associated genes in the striatum of subjects with obsessive-compulsive disorder Translational Psychiatry |
| title | Transcriptome alterations are enriched for synapse-associated genes in the striatum of subjects with obsessive-compulsive disorder |
| title_full | Transcriptome alterations are enriched for synapse-associated genes in the striatum of subjects with obsessive-compulsive disorder |
| title_fullStr | Transcriptome alterations are enriched for synapse-associated genes in the striatum of subjects with obsessive-compulsive disorder |
| title_full_unstemmed | Transcriptome alterations are enriched for synapse-associated genes in the striatum of subjects with obsessive-compulsive disorder |
| title_short | Transcriptome alterations are enriched for synapse-associated genes in the striatum of subjects with obsessive-compulsive disorder |
| title_sort | transcriptome alterations are enriched for synapse associated genes in the striatum of subjects with obsessive compulsive disorder |
| url | https://doi.org/10.1038/s41398-021-01290-1 |
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