Divergent Transcriptomic Effects of Allopregnanolone in Postpartum Depression
Brexanolone, a formulation of the neurosteroid allopregnanolone (ALLO), is approved for treating postpartum depression (PPD) and is being investigated for therapeutic efficacy across numerous neuropsychiatric disorders. Given ALLO’s beneficial effects on mood in women with PPD compared to healthy co...
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| Format: | Article |
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MDPI AG
2023-06-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/14/6/1234 |
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| author | Sarah A. Rudzinskas Maria A. Mazzu Crystal Edler Schiller Samantha Meltzer-Brody David R. Rubinow Peter J. Schmidt David Goldman |
| author_facet | Sarah A. Rudzinskas Maria A. Mazzu Crystal Edler Schiller Samantha Meltzer-Brody David R. Rubinow Peter J. Schmidt David Goldman |
| author_sort | Sarah A. Rudzinskas |
| collection | DOAJ |
| description | Brexanolone, a formulation of the neurosteroid allopregnanolone (ALLO), is approved for treating postpartum depression (PPD) and is being investigated for therapeutic efficacy across numerous neuropsychiatric disorders. Given ALLO’s beneficial effects on mood in women with PPD compared to healthy control women, we sought to characterize and compare the cellular response to ALLO in women with (<i>n</i> = 9) or without (<i>n</i> = 10, i.e., Controls) past PPD, utilizing our previously established patient-derived lymphoblastoid cell lines (LCLs). To mimic in vivo PPD ALLO-treatment, LCLs were exposed to ALLO or DMSO vehicle for 60 h and RNA-sequenced to detect differentially expressed genes (DEGs, p<sub>nominal</sub> < 0.05). Between ALLO-treated Control and PPD LCLs, 269 DEGs were identified, including Glutamate Decarboxylase 1 (<i>GAD1</i>), which was decreased 2-fold in PPD. Network analysis of PPD:ALLO DEGs revealed enriched terms related to synaptic activity and cholesterol biosynthesis. Within-diagnosis analyses (i.e., DMSO vs. ALLO) detected 265 ALLO-induced DEGs in Control LCLs compared to only 98 within PPD LCLs, with just 11 DEGs overlapping. Likewise, the gene ontologies underlying ALLO-induced DEGs in PPD and Control LCLs were divergent. These data suggest that ALLO may activate unique and opposing molecular pathways in women with PPD, which may be tied to its antidepressant mechanism. |
| first_indexed | 2024-03-11T02:25:08Z |
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| id | doaj.art-21bff24c4d634898a0514eeedbd2f031 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-11T02:25:08Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-21bff24c4d634898a0514eeedbd2f0312023-11-18T10:34:39ZengMDPI AGGenes2073-44252023-06-01146123410.3390/genes14061234Divergent Transcriptomic Effects of Allopregnanolone in Postpartum DepressionSarah A. Rudzinskas0Maria A. Mazzu1Crystal Edler Schiller2Samantha Meltzer-Brody3David R. Rubinow4Peter J. Schmidt5David Goldman6Behavioral Endocrinology Branch, National Institute of Mental Health (NIMH), NIH, 10 Center Drive MSC 1277, Bethesda, MD 20892, USABehavioral Endocrinology Branch, National Institute of Mental Health (NIMH), NIH, 10 Center Drive MSC 1277, Bethesda, MD 20892, USADepartment of Psychiatry, University of North Carolina, Chapel Hill, NC 27599, USADepartment of Psychiatry, University of North Carolina, Chapel Hill, NC 27599, USADepartment of Psychiatry, University of North Carolina, Chapel Hill, NC 27599, USABehavioral Endocrinology Branch, National Institute of Mental Health (NIMH), NIH, 10 Center Drive MSC 1277, Bethesda, MD 20892, USALaboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH, Rockville, MD 20855, USABrexanolone, a formulation of the neurosteroid allopregnanolone (ALLO), is approved for treating postpartum depression (PPD) and is being investigated for therapeutic efficacy across numerous neuropsychiatric disorders. Given ALLO’s beneficial effects on mood in women with PPD compared to healthy control women, we sought to characterize and compare the cellular response to ALLO in women with (<i>n</i> = 9) or without (<i>n</i> = 10, i.e., Controls) past PPD, utilizing our previously established patient-derived lymphoblastoid cell lines (LCLs). To mimic in vivo PPD ALLO-treatment, LCLs were exposed to ALLO or DMSO vehicle for 60 h and RNA-sequenced to detect differentially expressed genes (DEGs, p<sub>nominal</sub> < 0.05). Between ALLO-treated Control and PPD LCLs, 269 DEGs were identified, including Glutamate Decarboxylase 1 (<i>GAD1</i>), which was decreased 2-fold in PPD. Network analysis of PPD:ALLO DEGs revealed enriched terms related to synaptic activity and cholesterol biosynthesis. Within-diagnosis analyses (i.e., DMSO vs. ALLO) detected 265 ALLO-induced DEGs in Control LCLs compared to only 98 within PPD LCLs, with just 11 DEGs overlapping. Likewise, the gene ontologies underlying ALLO-induced DEGs in PPD and Control LCLs were divergent. These data suggest that ALLO may activate unique and opposing molecular pathways in women with PPD, which may be tied to its antidepressant mechanism.https://www.mdpi.com/2073-4425/14/6/1234postpartum depressionallopregnanolonetranscriptomicsneurosteroids<i>GAD1</i> |
| spellingShingle | Sarah A. Rudzinskas Maria A. Mazzu Crystal Edler Schiller Samantha Meltzer-Brody David R. Rubinow Peter J. Schmidt David Goldman Divergent Transcriptomic Effects of Allopregnanolone in Postpartum Depression Genes postpartum depression allopregnanolone transcriptomics neurosteroids <i>GAD1</i> |
| title | Divergent Transcriptomic Effects of Allopregnanolone in Postpartum Depression |
| title_full | Divergent Transcriptomic Effects of Allopregnanolone in Postpartum Depression |
| title_fullStr | Divergent Transcriptomic Effects of Allopregnanolone in Postpartum Depression |
| title_full_unstemmed | Divergent Transcriptomic Effects of Allopregnanolone in Postpartum Depression |
| title_short | Divergent Transcriptomic Effects of Allopregnanolone in Postpartum Depression |
| title_sort | divergent transcriptomic effects of allopregnanolone in postpartum depression |
| topic | postpartum depression allopregnanolone transcriptomics neurosteroids <i>GAD1</i> |
| url | https://www.mdpi.com/2073-4425/14/6/1234 |
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