# Mycophenolate mofetil reduces the branching of microglial processes

## TL;DR

This study shows that mycophenolate mofetil reduces microglial branching in the brain, affecting their complexity and diversity without altering proliferation.

## Contribution

The study reveals a novel role of guanosine nucleotides in regulating microglial branching through RhoA and Rac1 GTPases.

## Key findings

- MMF administration reduces microglial branching during postnatal development.
- MMF decreases brain guanosine nucleotides and GTP-bound RhoA and Rac1 levels.
- Microglial process length remains unaffected despite reduced branching.

## Abstract

Microglia, the resident immune cells in the central nervous system, play important roles not only in immune response but also in neurogenesis, synaptogenesis, and neural circuit formation. Microglia also surveil the brain environment via elongation and retraction of their processes. Previously, we found that the purine salvage pathway is involved in the regulation of morphology and dynamics of the microglial cell line BV2. Here, we show that intraperitoneal administration of mycophenolate mofetil (MMF), an inosine monophosphate dehydrogenase (IMPDH) inhibitor, reduces microglial branching during postnatal development. Imaging mass spectrometry analysis revealed that MMF administration decreases guanosine nucleotides in the brain. Interestingly, despite the essential role of guanosine nucleotides in cellular proliferation, MMF administration did not significantly affect microglial proliferation. On the other hand, MMF administration attenuated the level of GTP-bound forms of RhoA and Rac1 small GTPases. Notably, MMF administration decreased the number of branches, while process length remained unaffected. Since microglial branching affects microglial complexity and diversity, our findings suggest that guanosine nucleotide production is essential for generating proper microglial diversity.

The online version contains supplementary material available at 10.1186/s13041-025-01271-1.