Magnesium Transporter SLC41A1 Links Magnesium Homeostasis to NMDA Receptor-Related Synaptic Dysfunction: A Transdiagnostic Therapeutic Target for Neuropsychiatric Disorders.

Overview

1. Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou 510370, China; (X.C.); (W.D.); (X.C.)
2. The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou 510370, China
3. Department of Clinical Psychology, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou 510370, China
4. Institute of Psycho-Neuroscience, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou 510370, China

Abstract

Background: Neuropsychiatric disorders such as Alzheimer’s disease (AD), bipolar disorder (BD), and depression exhibit shared glutamatergic abnormalities, although their upstream molecular mechanisms remain poorly defined. Magnesium (Mg2+) serves as a key regulator of N-methyl-D-aspartate (NMDA) receptor function; however, the role of Mg2+ transporters, particularly SLC41A1, has not been systematically investigated. As NMDA receptor dysregulation contributes to emotional and cognitive impairments, elucidating Mg2+-NMDA signaling may enable the development of novel therapeutic strategies. Methods: We integrated Mendelian randomization, locus colocalization, human brain transcriptomics, functional enrichment, and co-expression analyses to determine whether SLC41A1 functions as a cross-disorder molecular driver. In addition, in vitro electrophysiological experiments using field potential recordings in hippocampal Schaffer-CA1 synapses were conducted to validate its functional role in NMDA receptor-mediated synaptic transmission. Results: Genetically elevated SLC41A1 expression increased the risk of AD, BD, depression, and alcohol dependence, with strong colocalization analyses supporting shared causal variants. Transcriptomic profiling revealed SLC41A1 upregulation in AD and BD, with enrichment in magnesium transport, mitochondrial function, and synaptic signaling pathways. Co-expression networks across GTEx brain regions demonstrated strong correlations with NMDA-related genes (e.g., GRINA, CAMK2G, GRIN2C). Under NMDAR-selective recording conditions, both imipramine treatment and SLC41A1 knockdown significantly reduced NMDAR-mediated fEPSP amplitudes, supporting a role for SLC41A1 in regulating NMDA receptor-dependent synaptic responses. Conclusions: This study identifies SLC41A1 as a magnesium-centered, transdiagnostic therapeutic target that links Mg2+ homeostasis to NMDA-dependent synaptic dysfunction. These findings provide a mechanistic foundation for developing SLC41A1-modulating or magnesium-based therapeutic approaches for mood and cognitive disorders.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE122063, at NCBI GEO; found in the text, “2.2. Data Sources”

Data Availability Statement

The datasets used in this study are available from public online repositories. Access details and accession numbers can be found in the article or Supplementary Materials. Animal data are available upon reasonable request from the corresponding author.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Recorded: type, language, journal, volume, issue, pages, dates, 4 authors, 6 keywords, 1 funder, 55 references.

Cite

This paper

Chen, X., Deng, W., Chen, X., & Yu, Y. (2026). Magnesium Transporter SLC41A1 Links Magnesium Homeostasis to NMDA Receptor-Related Synaptic Dysfunction: A Transdiagnostic Therapeutic Target for Neuropsychiatric Disorders. Biomedicines, 14(3), 610. https://doi.org/10.3390/biomedicines14030610

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