HMN 2026: How A common immunosuppressant may alter brain immune cells during early development

Researchers at University of Tsukuba have discovered that an immunosuppressive drug affects microglia, the resident immune cells of the brain. In mouse models, the drug reduced levels of guanosine nucleotides, which are essential for cell signaling and morphology. This reduction weakened the activity of small G proteins, leading to changes in microglial shape and function. The findings are published in the journal Molecular Brain.

Microglia are resident immune cells in the central nervous system that participate in the regulation of brain homeostasis throughout life. In early postnatal stages, microglia regulate neural circuit formation, debris clearance, and cerebral vasculature development. Microglia undergo morphological changes during brain development, giving rise to functionally diverse subpopulations. However, the molecular mechanisms underlying these morphological changes have not been fully elucidated.

The research team previously found that purine metabolism regulates microglial morphology. Purine metabolism encompasses the pathways that process purine bases, including adenine and guanine, and it is essential for energy production and nucleic acid synthesis.

In the current study, the team focused on inosine monophosphate (IMP), a key metabolic intermediate that serves as a precursor for adenosine triphosphate and guanosine triphosphate (GTP). Administration of mycophenolate mofetil (MMF), which inhibits IMP conversion, resulted in reduced levels of guanosine nucleotides in the brain, accompanied by decreased activation of small G proteins that regulate the cytoskeleton. Consistently, microglia exhibited fewer cellular processes and reduced morphological complexity.

Microglia continuously extend and retract their processes to sense and communicate with their surrounding environment. Therefore, elucidating the mechanisms governing morphological alterations in microglia may provide critical insights into neurodevelopmental disorders associated with impaired microglial function. These findings further suggest that MMF, a well-established immunosuppressant, could be repurposed to modulate microglial activity, potentially facilitating the development of novel therapeutic strategies targeting microglia.

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