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PMID: 37715107 Published · ppublish English Journal Article

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

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology ·Vol. 49 ·No. 2 ·2024-01-00 ·Pages 433-442

Zhou DY, Su X, Wu Y, Yang Y, Zhang L, Cheng S, Shao M, Li W, Zhang Z, Wang L, Lv L, Li M, Song M

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.

MeSH Terms
Humans Mice Animals Schizophrenia Genome-Wide Association Study/methods Genetic Predisposition to Disease/genetics Dendritic Spines/metabolism Prefrontal Cortex/metabolism Cognition Sensory Gating Morphogenesis Polymorphism, Single Nucleotide/genetics Cation Transport Proteins/genetics,metabolism
Chemicals
CNNM2 protein, human Cation Transport Proteins
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Zhou Dan-Yang
Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China. | Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China.
Su Xi
Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China. | Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, Henan, China.
Wu Yong ORCID
Research Center for Mental Health and Neuroscience, Wuhan Mental Health Center, Wuhan, Hubei, China. | Affiliated Wuhan Mental Health Center, Jianghan University, Wuhan, Hubei, China.
Yang Yongfeng ORCID
Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China. | Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, Henan, China.
Zhang Luwen
Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China. | Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, Henan, China.
Cheng Shumin
Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China. | Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, Henan, China.
Shao Minglong
Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China. | Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, Henan, China.
Li Wenqiang ORCID
Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China. | Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, Henan, China.
Zhang Zhaohui
Department of Psychiatry, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.
Wang Lu
Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
Lv Luxian
Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China. | Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, Henan, China. | Henan Province People's Hospital, Zhengzhou, Henan, China.
Li Ming ORCID
Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China. [email protected]. | Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China. [email protected]. | KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China. [email protected].
Song Meng
Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China. [email protected]. | Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, Henan, China. [email protected].
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Article Info
Journal
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Abbr.
Neuropsychopharmacology
ISSN
1740-634X
DOI
10.1038/s41386-023-01732-y
Email
[email protected]
[email protected]
Published
2024-01-00
Epub
2023-00-15
Pages
433-442
Language
English
Region
England
NLM ID
8904907
PMCID
PMC10724213
Subset
IM
Grants
NIMH NIH HHS · R01 MH110928 · United States
NIMH NIH HHS · R56 MH114901 · United States
NIMH NIH HHS · U01 MH103365 · United States
NIMH NIH HHS · R01 MH110905 · United States
NIMH NIH HHS · U01 MH116489 · United States
NIMH NIH HHS · R21 MH109956 · United States
NIMH NIH HHS · U01 MH103346 · United States
NIMH NIH HHS · R56 MH114911 · United States
NIMH NIH HHS · U01 MH103339 · United States
NIMH NIH HHS · R01 MH110920 · United States
NIMH NIH HHS · U01 MH116487 · United States
NIMH NIH HHS · R21 MH105881 · United States
NIMH NIH HHS · R01 MH110921 · United States
NIMH NIH HHS · R01 MH110926 · United States
NIMH NIH HHS · U01 MH116488 · United States
NIMH NIH HHS · U01 MH116438 · United States
NIMH NIH HHS · U01 MH116442 · United States
NIMH NIH HHS · R01 MH094714 · United States
NIMH NIH HHS · R01 MH117292 · United States
NIMH NIH HHS · R21 MH103877 · United States
NIMH NIH HHS · R01 MH110927 · United States
NIMH NIH HHS · U01 MH116441 · United States
NIMH NIH HHS · R56 MH114899 · United States
NIMH NIH HHS · U01 MH103392 · United States
NIMH NIH HHS · R01 MH117291 · United States
NIMH NIH HHS · R01 MH117293 · United States
NIMH NIH HHS · R01 MH109677 · United States
NIMH NIH HHS · R01 MH111721 · United States
NIMH NIH HHS · U01 MH103340 · United States
NIMH NIH HHS · R21 MH102791 · United States
NIMH NIH HHS · R01 MH105898 · United States
NIMH NIH HHS · R21 MH105853 · United States
NIMH NIH HHS · R01 MH109715 · United States
NIMH NIH HHS · U01 MH116492 · United States
NIMH NIH HHS · P50 MH106934 · United States
External Links
PubMed source DOI: 10.1038/s41386-023-01732-y PMC Full Text View journal details
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