Journal
MOLECULAR NEUROBIOLOGY
Volume 56, Issue 9, Pages 6184-6196Publisher
SPRINGER
DOI: 10.1007/s12035-019-1502-9
Keywords
Microglial depletion; Clodronate liposomes; Inflammation
Categories
Funding
- National Institutes of Health [R01NS102583, R01NS105894]
- American Heart Association [17GRNT33660766, 16SDG30980031, 17POST33660191]
- Stimulating and Advancing ACCM Research (StAAR) Award from the Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University
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Investigators are increasingly interested in using microglial depletion to study the role of microglia under pathologic conditions. Liposome-encapsulated clodronate is commonly used to eliminate macrophage populations because it causes functionally irreversible inhibition and apoptosis once phagocytized by macrophages. Recent studies have shown that microglia can be depleted in disease models by injecting clodronate liposomes into the brain parenchyma. However, it is unclear whether intracerebral administration of clodronate liposomes is a practical method of eliminating microglia under physiologic conditions or whether microglial depletion induces damage to other brain cells. In this study, injecting 1 mu L of clodronate liposomes (7 mu g/mu L) into the striatum of mice caused ablation of microglia at 1 day that persisted for 3 days. Microglia reappeared in the boundary regions of microglia elimination after 5 days. Importantly, we observed an increase in proinflammatory cytokine levels and an increase in neural/glial antigen 2 and glial fibrillary acidic protein expression in the perilesional region. In contrast, expression levels of myelin basic protein, microtubule-associated protein 2, and postsynaptic protein-95 decreased in the periphery of regions where microglia were depleted. Moreover, clodronate liposome administration decreased the density and integrity of blood vessels in the perilesional regions. In cultured primary neurons, clodronate liposome exposure also attenuated ATP synthesis. Together, these findings suggest that intracerebral administration of clodronate liposomes into brain parenchyma can deplete microglia, but can also damage other brain cells and blood vessel integrity.
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