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

## TL;DR

This study shows that the magnesium transporter SLC41A1 is linked to NMDA receptor dysfunction in brain disorders like Alzheimer's and bipolar disorder, suggesting it could be a new treatment target.

## Contribution

The paper identifies SLC41A1 as a transdiagnostic therapeutic target connecting magnesium homeostasis to NMDA receptor-related synaptic dysfunction.

## Key findings

- Genetically elevated SLC41A1 expression increases the risk of Alzheimer’s disease, bipolar disorder, depression, and alcohol dependence.
- SLC41A1 knockdown and imipramine treatment reduced NMDA receptor-mediated synaptic responses in hippocampal synapses.
- SLC41A1 is enriched in magnesium transport and synaptic signaling pathways in Alzheimer’s and bipolar disorder.

## 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.