Proc. Natl Acad. Sci. USA 117, 6651–6662 (2020).

A role for immunopathology or immune cell involvement has been suspected for human psychiatric diseases such as depression. In The Proceedings of the National Academy of Sciences, Lago et al. show that the immunoreceptor CD300f can modulate microglial metabolism and synaptic pruning activity associated with depressive behaviors. They first identify a protective allele of CD300f that curiously only affects women. Female but not male mice deficient for CD300f likewise show depression-like behaviors but do not develop classical neuroinflammation. CD300f is expressed by microglia and perivascular macrophages; however, while transcriptional profiles are similar between naive wild-type and Cd300f–/– microglial cells, the latter have increased expression of Il6 and Il1rn and decreased expression of Spp1. Peripheral injury models induce profound metabolic differences in Cd300f–/– microglia as compared to wild-type cells, with reduced activation of glycolysis and oxidative phosphorylation pathways. In vitro assays show CD300f modulates neuronal synaptic strength. In vivo, hippocampal neurotransmission of noradrenaline was decreased, but synaptic serotonin and dopamine content remained unchanged. These findings show CD300f can influence the development of depressive behaviors, yet it remains unknown how sex influences CD300f activity.