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Decreased CNNM2 expression in prefrontal cortex affects sensorimotor gating function, cognition, dendritic spine morphogenesis and risk of schizophrenia

Neuropsychopharmacology volume 49, pages 433–442 (2024)Cite this article

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Abstract

Genome-wide association studies (GWASs) have reported multiple single nucleotide polymorphisms (SNPs) associated with schizophrenia, yet the underlying molecular mechanisms are largely unknown. In this study, we aimed to identify schizophrenia relevant genes showing alterations in mRNA and protein expression associated with risk SNPs at the 10q24.32-33 GWAS locus. We carried out the quantitative trait loci (QTL) and summary data-based Mendelian randomization (SMR) analyses, using the PsychENCODE dorsolateral prefrontal cortex (DLPFC) expression QTL (eQTL) database, as well as the ROSMAP and Banner DLPFC protein QTL (pQTL) datasets. The gene CNNM2 (encoding a magnesium transporter) at 10q24.32-33 was identified to be a robust schizophrenia risk gene, and was highly expressed in human neurons according to single cell RNA-seq (scRNA-seq) data. We further revealed that reduced Cnnm2 in the mPFC of mice led to impaired cognition and compromised sensorimotor gating function, and decreased Cnnm2 in primary cortical neurons altered dendritic spine morphogenesis, confirming the link between CNNM2 and endophenotypes of schizophrenia. Proteomics analyses showed that reduced Cnnm2 level changed expression of proteins associated with neuronal structure and function. Together, these results identify a robust gene in the pathogenesis of schizophrenia.

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Fig. 1: Genetic and molecular characterizations of 10q24.32-33 GWAS locus.
Fig. 2: SMR analyses through integrating schizophrenia PGC3 GWAS with different brain QTL datasets.
Fig. 3: Knockdown of Cnnm2 in the mPFC of mice results in behavioral abnormalities associated with schizophrenia.
Fig. 4: Knockdown of Cnnm2 expression in rat primary cortical neurons and their impacts on dendritic spine morphogenesis (n ≥ 70 neurons in each experimental group).
Fig. 5: overview of the altered proteome of mPFC in Cnnm2 knockdown mice.

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Acknowledgements

The authors sincerely acknowledge the important contributions of many publicly available datasets, including the PGC, the ROSMAP and Banner, and the PsychENCODE Consortium. We thank the participants of the ROS, MAP, Mayo, Mount Sinai Brain Bank and Banner Sun Health Research Institute Brain and Body Donation Program for their time and participation. Data were generated as part of the PsychENCODE Consortium, supported by: U01MH103392, U01MH103365, U01MH103346, U01MH103340, U01MH103339, R21MH109956, R21MH105881, R21MH105853, R21MH103877, R21MH102791, R01MH111721, R01MH110928, R01MH110927, R01MH110926, R01MH110921, R01MH110920, R01MH110905, R01MH109715, R01MH109677, R01MH105898, R01MH105898, R01MH094714, P50MH106934, U01MH116488, U01MH116487, U01MH116492, U01MH116489, U01MH116438, U01MH116441, U01MH116442, R01MH114911, R01MH114899, R01MH114901, R01MH117293, R01MH117291, R01MH117292 awarded to: Schahram Akbarian (Icahn School of Medicine at Mount Sinai), Gregory Crawford (Duke University), Stella Dracheva (Icahn School of Medicine at Mount Sinai), Peggy Farnham (University of Southern California), Mark Gerstein (Yale University), Daniel Geschwind (University of California, Los Angeles), Fernando Goes (Johns Hopkins University), Thomas M. Hyde (Lieber Institute for Brain Development), Andrew Jaffe (Lieber Institute for Brain Development), James A. Knowles (University of Southern California), Chunyu Liu (SUNY Upstate Medical University), Dalila Pinto (Icahn School of Medicine at Mount Sinai), Panos Roussos (Icahn School of Medicine at Mount Sinai), Stephan Sanders (University of California, San Francisco), Nenad Sestan (Yale University), Pamela Sklar (Icahn School of Medicine at Mount Sinai), Matthew State (University of California, San Francisco), Patrick Sullivan (University of North Carolina), Flora Vaccarino (Yale University), Daniel Weinberger (Lieber Institute for Brain Development), Sherman Weissman (Yale University), Kevin White (University of Chicago), Jeremy Willsey (University of California, San Francisco), and Peter Zandi (Johns Hopkins University).

Funding

This work was supported by grants from the National Natural Science Foundation of China (U22A20304 and 81971252 to LXL, 82001407 to XS, 32100482 to LW, 81903688 to MLS), Science and Technology Project of Henan Province (212102310587 to MS, 222102310130 to XS), Spring City Plan: the High-level Talent Promotion and Training Project of Kunming (2022SCP001), Yunnan Fundamental Research Projects (202101AT070283 to LW), Youth Project of Medical Science and Technology of Henan Province (SBGJ202103094 to XS), Open Project of Henan Key Laboratory of Biological Psychiatry (ZDSYS2022002 to MS), High Scientific and Technological Research Fund of Xinxiang Medical University (2017ZDCG-04 to LXL), Major Science and Technology Projects of Henan Province (201300310200 to LXL), Project (joint construction) of Medical Science and Technology in Henan Province (LHGJ20190475 to MLS).

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  1. These authors contributed equally: Dan-Yang Zhou, Xi Su.

Authors and Affiliations

  1. Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China

    Dan-Yang Zhou, Lu Wang & Ming Li

  2. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China

    Dan-Yang Zhou & Ming Li

  3. Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China

    Xi Su, Yongfeng Yang, Luwen Zhang, Shumin Cheng, Minglong Shao, Wenqiang Li, Luxian Lv & Meng Song

  4. Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, Henan, China

    Xi Su, Yongfeng Yang, Luwen Zhang, Shumin Cheng, Minglong Shao, Wenqiang Li, Luxian Lv & Meng Song

  5. Research Center for Mental Health and Neuroscience, Wuhan Mental Health Center, Wuhan, Hubei, China

    Yong Wu

  6. Affiliated Wuhan Mental Health Center, Jianghan University, Wuhan, Hubei, China

    Yong Wu

  7. Department of Psychiatry, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China

    Zhaohui Zhang

  8. Henan Province People’s Hospital, Zhengzhou, Henan, China

    Luxian Lv

  9. KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China

    Ming Li

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Contributions

ML, LXL and MS designed the study and interpreted the results. DYZ, XS and YW performed the primary experiments and analyses. YFY, LWZ, SMC, MLS, WQL, ZHZ and LW contributed to the analyses and results interpretation. DYZ, MS, ML and XS drafted the first manuscript, and all authors contributed to the final version of the paper.

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Correspondence to Ming Li or Meng Song.

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Zhou, DY., Su, X., Wu, Y. et al. Decreased CNNM2 expression in prefrontal cortex affects sensorimotor gating function, cognition, dendritic spine morphogenesis and risk of schizophrenia. Neuropsychopharmacol. 49, 433–442 (2024). https://doi.org/10.1038/s41386-023-01732-y

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