Exploring PDE5A upregulation in bipolar disorder: insights from single-nucleus RNA sequencing of human basal ganglia
Abstract Basal ganglia is proposed to mediate symptoms underlying bipolar disorder (BD). To understand the cell type-specific gene expression and network changes of BD basal ganglia, we performed single-nucleus RNA sequencing of 30,752 nuclei from caudate, putamen, globus pallidus, and substantia ni...
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Nature Publishing Group
2024-12-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-024-03202-5 |
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| author | Zhixin Bai Peilong Li Xu Gao Gaoyu Zu Andrew Jiang Keting Wu Naguib Mechawar Gustavo Turecki Klaus Lehnert Russell G. Snell Jin Zhou Jia Hu Bingbing Yan Liang Chen Wensheng Li You Chen Shuai Liu Ying Zhu Linya You |
| author_facet | Zhixin Bai Peilong Li Xu Gao Gaoyu Zu Andrew Jiang Keting Wu Naguib Mechawar Gustavo Turecki Klaus Lehnert Russell G. Snell Jin Zhou Jia Hu Bingbing Yan Liang Chen Wensheng Li You Chen Shuai Liu Ying Zhu Linya You |
| author_sort | Zhixin Bai |
| collection | DOAJ |
| description | Abstract Basal ganglia is proposed to mediate symptoms underlying bipolar disorder (BD). To understand the cell type-specific gene expression and network changes of BD basal ganglia, we performed single-nucleus RNA sequencing of 30,752 nuclei from caudate, putamen, globus pallidus, and substantia nigra of control human postmortem brain and 24,672 nuclei from BD brain. Differential expression analysis revealed major difference lying in caudate, with BD medium spiny neurons (MSNs) expressing significantly higher PDE5A, a cGMP-specific phosphodiesterase. Gene co-expression analysis (WGCNA) showed a strong correlation of caudate MSNs and gene module green, with a PDE5A-containing hub gene network. Gene regulatory network analysis (SCENIC) indicated key regulons among different cell types and basal ganglia regions, with downstream targets of key transcriptional factors showing overlapping genes such as PDEs. Upregulation of PDE5A was further validated in 7 pairs of control and BD caudate sections. Overexpression of PDE5A in primary cultured lateral ganglion eminence-derived striatal neurons led to decreased dendrite complexity, increased apoptosis, and enhanced neuronal excitability and membrane resistance. This effect could be rescued by PDE5 specific inhibitor, tadalafil. Overexpression of PDE5A in mouse striatum by stereotaxic injection caused a decreased cGMP level, an increased gene expression profile of neuroinflammation, and BD-like behaviors. Collectively, our findings provided cell type-specific gene expression profile, and indicated a causative role of PDE5A upregulation in BD basal ganglia. This study provides a single-nucleus transcriptomic profile of human control and bipolar disorder (BD) basal ganglia. Differential expression, gene co-expression, and gene regulatory network analyses collectively indicated upregulation of PDE5A in BD caudate medium spiny neurons (MSNs), which was further validated in another cohort of BD brains. The causative role of PDE5A upregulation in BD etiology is supported by the effects of PDE5A overexpression in cultured mouse MSNs in vitro and in adult mouse striatum in vivo. The former led to reduced dendrite complexity, increased apoptosis, and neuronal hyper-excitability, which could be rescued by PDE5 specific inhibitor tadalafil. The latter caused lower cGMP levels, upregulated genes associated with neuroinflammation, and BD-like behaviors. |
| format | Article |
| id | doaj-art-8ebf723ea0fe4022bf1f04ce0812915f |
| institution | OA Journals |
| issn | 2158-3188 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Publishing Group |
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| series | Translational Psychiatry |
| spelling | doaj-art-8ebf723ea0fe4022bf1f04ce0812915f2025-08-20T01:57:12ZengNature Publishing GroupTranslational Psychiatry2158-31882024-12-0114111910.1038/s41398-024-03202-5Exploring PDE5A upregulation in bipolar disorder: insights from single-nucleus RNA sequencing of human basal gangliaZhixin Bai0Peilong Li1Xu Gao2Gaoyu Zu3Andrew Jiang4Keting Wu5Naguib Mechawar6Gustavo Turecki7Klaus Lehnert8Russell G. Snell9Jin Zhou10Jia Hu11Bingbing Yan12Liang Chen13Wensheng Li14You Chen15Shuai Liu16Ying Zhu17Linya You18Department of Human Anatomy & Histoembryology, School of Basic Medical Sciences, Fudan UniversityState Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, and Department of Neurosurgery, Huashan Hospital, Fudan UniversityShanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Affiliated Mental Health Center (ECNU), School of Psychology and Cognitive Science, East China Normal UniversityDepartment of Human Anatomy & Histoembryology, School of Basic Medical Sciences, Fudan UniversityApplied Translational Genetics Group, School of Biological Sciences, the University of AucklandDepartment of Human Anatomy & Histoembryology, School of Basic Medical Sciences, Fudan UniversityMcGill Group for Suicide Studies, Douglas Mental Health University InstituteMcGill Group for Suicide Studies, Douglas Mental Health University InstituteApplied Translational Genetics Group, School of Biological Sciences, the University of AucklandApplied Translational Genetics Group, School of Biological Sciences, the University of AucklandShanghai Yangpu District Mental Health Center, Mental Health Center Affiliated to Shanghai University of Medicine & Health SciencesShanghai Yangpu District Mental Health Center, Mental Health Center Affiliated to Shanghai University of Medicine & Health SciencesNeo-Biotechnology Limited CompanyDepartment of Human Anatomy & Histoembryology, School of Basic Medical Sciences, Fudan UniversityDepartment of Human Anatomy & Histoembryology, School of Basic Medical Sciences, Fudan UniversityShanghai Yangpu District Mental Health Center, Mental Health Center Affiliated to Shanghai University of Medicine & Health SciencesShanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Affiliated Mental Health Center (ECNU), School of Psychology and Cognitive Science, East China Normal UniversityState Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, and Department of Neurosurgery, Huashan Hospital, Fudan UniversityDepartment of Human Anatomy & Histoembryology, School of Basic Medical Sciences, Fudan UniversityAbstract Basal ganglia is proposed to mediate symptoms underlying bipolar disorder (BD). To understand the cell type-specific gene expression and network changes of BD basal ganglia, we performed single-nucleus RNA sequencing of 30,752 nuclei from caudate, putamen, globus pallidus, and substantia nigra of control human postmortem brain and 24,672 nuclei from BD brain. Differential expression analysis revealed major difference lying in caudate, with BD medium spiny neurons (MSNs) expressing significantly higher PDE5A, a cGMP-specific phosphodiesterase. Gene co-expression analysis (WGCNA) showed a strong correlation of caudate MSNs and gene module green, with a PDE5A-containing hub gene network. Gene regulatory network analysis (SCENIC) indicated key regulons among different cell types and basal ganglia regions, with downstream targets of key transcriptional factors showing overlapping genes such as PDEs. Upregulation of PDE5A was further validated in 7 pairs of control and BD caudate sections. Overexpression of PDE5A in primary cultured lateral ganglion eminence-derived striatal neurons led to decreased dendrite complexity, increased apoptosis, and enhanced neuronal excitability and membrane resistance. This effect could be rescued by PDE5 specific inhibitor, tadalafil. Overexpression of PDE5A in mouse striatum by stereotaxic injection caused a decreased cGMP level, an increased gene expression profile of neuroinflammation, and BD-like behaviors. Collectively, our findings provided cell type-specific gene expression profile, and indicated a causative role of PDE5A upregulation in BD basal ganglia. This study provides a single-nucleus transcriptomic profile of human control and bipolar disorder (BD) basal ganglia. Differential expression, gene co-expression, and gene regulatory network analyses collectively indicated upregulation of PDE5A in BD caudate medium spiny neurons (MSNs), which was further validated in another cohort of BD brains. The causative role of PDE5A upregulation in BD etiology is supported by the effects of PDE5A overexpression in cultured mouse MSNs in vitro and in adult mouse striatum in vivo. The former led to reduced dendrite complexity, increased apoptosis, and neuronal hyper-excitability, which could be rescued by PDE5 specific inhibitor tadalafil. The latter caused lower cGMP levels, upregulated genes associated with neuroinflammation, and BD-like behaviors.https://doi.org/10.1038/s41398-024-03202-5 |
| spellingShingle | Zhixin Bai Peilong Li Xu Gao Gaoyu Zu Andrew Jiang Keting Wu Naguib Mechawar Gustavo Turecki Klaus Lehnert Russell G. Snell Jin Zhou Jia Hu Bingbing Yan Liang Chen Wensheng Li You Chen Shuai Liu Ying Zhu Linya You Exploring PDE5A upregulation in bipolar disorder: insights from single-nucleus RNA sequencing of human basal ganglia Translational Psychiatry |
| title | Exploring PDE5A upregulation in bipolar disorder: insights from single-nucleus RNA sequencing of human basal ganglia |
| title_full | Exploring PDE5A upregulation in bipolar disorder: insights from single-nucleus RNA sequencing of human basal ganglia |
| title_fullStr | Exploring PDE5A upregulation in bipolar disorder: insights from single-nucleus RNA sequencing of human basal ganglia |
| title_full_unstemmed | Exploring PDE5A upregulation in bipolar disorder: insights from single-nucleus RNA sequencing of human basal ganglia |
| title_short | Exploring PDE5A upregulation in bipolar disorder: insights from single-nucleus RNA sequencing of human basal ganglia |
| title_sort | exploring pde5a upregulation in bipolar disorder insights from single nucleus rna sequencing of human basal ganglia |
| url | https://doi.org/10.1038/s41398-024-03202-5 |
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