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KCNH2-3.1 mediates aberrant complement activation and impaired hippocampal-medial prefrontal circuitry associated with working memory deficits

Molecular Psychiatry volume 25, pages 206–229 (2020)Cite this article

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Abstract

Increased expression of the 3.1 isoform of the KCNH2 potassium channel has been associated with cognitive dysfunction and with schizophrenia, yet little is known about the underlying pathophysiological mechanisms. Here, by using in vivo wireless local field potential recordings during working memory processing, in vitro brain slice whole-cell patching recordings and in vivo stereotaxic hippocampal injection of AAV-encoded expression, we identified specific and delayed disruption of hippocampal-mPFC synaptic transmission and functional connectivity associated with reductions of SERPING1, CFH, and CD74 in the KCNH2-3.1 overexpression transgenic mice. The differentially expressed genes in mice are enriched in neurons and microglia, and reduced expression of these genes dysregulates the complement cascade, which has been previously linked to synaptic plasticity. We find that knockdown of these genes in primary neuronal–microglial cocultures from KCNH2-3.1 mice impairs synapse formation, and replenishing reduced CFH gene expression rescues KCNH2-3.1-induced impaired synaptogenesis. Translating to humans, we find analogous dysfunctional interactions between hippocampus and prefrontal cortex in coupling of the fMRI blood oxygen level-dependent (BOLD) signal during working memory in healthy subjects carrying alleles associated with increased KCNH2-3.1 expression in brain. Our data uncover a previously unrecognized role of the truncated KCNH2-3.1 potassium channel in mediating complement activation, which may explain its association with altered hippocampal–prefrontal connectivity and synaptic function. These results provide a potential molecular link between increased KCNH2-3.1 expression, synapse alterations, and hippocampal–prefrontal circuit abnormalities implicated in schizophrenia.

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Data availability

Sequencing data have been submitted to the GEO repository under accession numbers GSE118989 (for all RNA-seq data).

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Acknowledgements

This study was funded by the National Institute of Mental Health (NIMH) R01MH101102 (FY). FY was also supported by Department of Defense (DoD) CDMRP W81XWH-16-2-0002. Lieber Institute also supported this study. The authors wish to thank the Lieber Institute founders, C. Lieber, S. Lieber and S. Lieber, T. Maltz and M. Maltz, for their vision, encouragement and support. We thank Brady Maher, Keri Martinowich, and Zhibin Wang for the thoughtful comments and suggestions. We also thank M. Pucak for the technical support of the Imaris software confocal image processing (Imaging Core was partially supported by an NINDS Core Center Grant P30 NS050274). We are grateful for the technical support of the many staff members in the Lieber Institute for Brain Development who are not part of the authorship of this paper.

Author information

Author notes

  1. Zhonghua Hu

    Present address: Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China

  2. Feng Yang

    Present address: Advanced Innovation Center for Human Brain Protection, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

  3. These authors contributed equally: Ming Ren, Zhonghua Hu, Qiang Chen

Authors and Affiliations

  1. Lieber Institute for Brain Development, Johns Hopkins University Medical Center, Baltimore, MD, USA

    Ming Ren, Zhonghua Hu, Qiang Chen, Andrew Jaffe, Yingbo Li, Vijay Sadashivaiah, Shujuan Zhu, Nina Rajpurohit, Joo Heon Shin, Wei Xia, Yankai Jia, Jingxian Wu, Sunny Lang Qin, Jian Zhu, Qingjun Tian, Daniel Paredes, Fengyu Zhang, Venkata S. Mattay, Daniel R. Weinberger & Feng Yang

  2. Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Andrew Jaffe

  3. Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Andrew Jaffe

  4. Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA

    Andrew Jaffe

  5. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Andrew Jaffe & Daniel R. Weinberger

  6. Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Andrew Jaffe & Daniel R. Weinberger

  7. Institute of Neuroscience, Chongqing Medical University, Chongqing, China

    Yingbo Li, Shujuan Zhu & Jingxian Wu

  8. Department of Physiology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, China

    Yingbo Li

  9. Unit on Neural Circuits and Adaptive Behaviours, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Bethesda, MD, USA

    Xinjian Li & Kuan Hong Wang

  10. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Daniel Paredes & Venkata S. Mattay

  11. Department of Radiology, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Venkata S. Mattay & Daniel R. Weinberger

  12. Section on Integrative Neuroimaging and the Clinical Brain Disorders Branch, National Institute of Mental Health, Bethesda, MD, USA

    Joseph H. Callicott & Karen F. Berman

  13. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Daniel R. Weinberger

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Contributions

FY and DRW conceived the study and organized the entire research. RM, ZH, QC, ZW, FY, and DRW designed the study. RM, FY, QC, YL, SZ, and VS performed T-maze and the LFPs experiments and analysed the data, assisted by ZH, SLQ, XL, JZ, QT, DP, and KHW; VSM, JHC, and KFB performed the fMRI data collection; QC performed the fMRI analysis; RM conducted all whole-cell patch recording, RM and FY analyzed electrophysiological data; ZH assisted by JW conducted the molecular biology and morphology experiments, and data analyses in this study; ZH assisted by QT made all RNA-seq libraries; WX and YJ carried out the RNA-seq preparation and sequencing; AJ, NR, and JHS performed RNA-seq data analysis; ZH performed neuronal and microglial gene expression assay; MR, ZH, QC, AJ, DRW, and FY wrote the manuscript. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Daniel R. Weinberger or Feng Yang.

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Ren, M., Hu, Z., Chen, Q. et al. KCNH2-3.1 mediates aberrant complement activation and impaired hippocampal-medial prefrontal circuitry associated with working memory deficits. Mol Psychiatry 25, 206–229 (2020). https://doi.org/10.1038/s41380-019-0530-1

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  • DOI: https://doi.org/10.1038/s41380-019-0530-1

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