When microglia become overactivated, they release excessive amounts of glutamate, a chemical messenger that can damage neurons and contribute to the development of depressive symptoms. At the centre of this process is an enzyme called glutaminase, which drives the production of that excess glutamate.

Zhu’s team had previously noticed that glutaminase is significantly more active in the microglia of people with depression. The question was how to dial it down safely. Existing drugs that block glutaminase either struggle to cross into the brain or cause unpleasant gastrointestinal side effects – a major barrier to their clinical use.

The solution the team developed is elegant in its precision. Slusher and her drug discovery colleagues from the Institute of Organic Chemistry and Biochemistry in Prague and the Center for Nanomedicine at Johns Hopkins attached two glutaminase-blocking drugs to tiny nanoparticles called hydroxyl-dendrimers, which have a remarkable natural ability to be absorbed specifically by activated microglia.

Think of the dendrimer as a targeted delivery vehicle, carrying its therapeutic cargo directly to the cells that need it, while leaving healthy tissue untouched.

Testing the approach in mice exposed to chronic social stress – a well-established model for depression – Zhu, Slusher, and their colleagues found that the dendrimer-drug conjugates successfully reduced glutaminase activity in microglia without affecting other cell types.

The treated mice showed meaningful improvements in social behaviour and reduced anxiety. The lead compound tested also improved recognition memory and importantly did not cause any gastrointestinal damage, addressing one of the key safety concerns that has plagued earlier glutaminase inhibitors.

Drs. Zhu and Slusher are clear-eyed about what remains to be done. The experiments so far have been conducted only in male mice, and the team acknowledges that further work is needed to understand how this treatment might perform across sexes and in human clinical trials. Still, this work opens a genuinely new direction in depression research – one that treats the brain’s inflammatory processes, not just its chemistry.