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  3. Exploring PDE5A upregulation in bipolar disorder: insights from single-nucleus RNA sequencing of human basal ganglia

Exploring PDE5A upregulation in bipolar disorder: insights from single-nucleus RNA sequencing of human basal ganglia

  • Transl Psychiatry. 2024 Dec 18;14(1):494. doi: 10.1038/s41398-024-03202-5.
Zhixin Bai # 1,  Peilong Li # 2,  Xu Gao # 3 4 5,  Gaoyu Zu 1,  Andrew Jiang 6,  Keting Wu 1,  Naguib Mechawar 7 8,  Gustavo Turecki 7 8,  Klaus Lehnert 6,  Russell G Snell 6,  Jin Zhou 9,  Jia Hu 9,  Bingbing Yan 10,  Liang Chen 1,  Wensheng Li 1,  You Chen 11,  Shuai Liu 12 13 14,  Ying Zhu 15,  Linya You 16 17
Affiliations

Affiliations

  • 1 Department of Human Anatomy & Histoembryology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 2 State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, and Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
  • 3 Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Affiliated Mental Health Center (ECNU), School of Psychology and Cognitive Science, East China Normal University, Shanghai, China.
  • 4 Shanghai Changning Mental Health Center, Shanghai, China.
  • 5 NYU-ECNU Institute of Brain and Cognitive Science at NYU Shanghai, Shanghai, China.
  • 6 Applied Translational Genetics Group, School of Biological Sciences, the University of Auckland, Auckland, New Zealand.
  • 7 McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, QC, Canada.
  • 8 Department of Psychiatry, McGill University, Montreal, QC, Canada.
  • 9 Shanghai Yangpu District Mental Health Center, Mental Health Center Affiliated to Shanghai University of Medicine & Health Sciences, Shanghai, China.
  • 10 Neo-Biotechnology Limited Company, Shanghai, China.
  • 11 Shanghai Yangpu District Mental Health Center, Mental Health Center Affiliated to Shanghai University of Medicine & Health Sciences, Shanghai, China. yangpucy@163.com.
  • 12 Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Affiliated Mental Health Center (ECNU), School of Psychology and Cognitive Science, East China Normal University, Shanghai, China. sliu@psy.ecnu.edu.cn.
  • 13 Shanghai Changning Mental Health Center, Shanghai, China. sliu@psy.ecnu.edu.cn.
  • 14 NYU-ECNU Institute of Brain and Cognitive Science at NYU Shanghai, Shanghai, China. sliu@psy.ecnu.edu.cn.
  • 15 State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, and Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China. ying_zhu@fudan.edu.cn.
  • 16 Department of Human Anatomy & Histoembryology, School of Basic Medical Sciences, Fudan University, Shanghai, China. lyyou@fudan.edu.cn.
  • 17 Key Laboratory of Medical Imaging Computing and Computer Assisted Intervention of Shanghai, Fudan University, Shanghai, China. lyyou@fudan.edu.cn.
  • # Contributed equally.
PMID: 39695100 DOI: 10.1038/s41398-024-03202-5
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.

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