CD300f immunoreceptor is associated with major depressive disorder and decreased microglial metabolic fitness

Abstract

A role for microglia in neuropsychiatric diseases, including major depressive disorder (MDD), has been postulated. Regulation of microglial phenotype by immune receptors has become a central topic in many neurological conditions. We explored preclinical and clinical evidence for the role of the CD300f immune receptor in the fine regulation of microglial phenotype and its contribution to MDD. We found that a prevalent nonsynonymous single-nucleotide polymorphism (C/T, rs2034310) of the human CD300f receptor cytoplasmic tail inhibits the protein kinase C phosphorylation of a threonine and is associated with protection against MDD, mainly in women. Interestingly, CD300f^−/− mice displayed several characteristic MDD traits such as augmented microglial numbers, increased interleukin 6 and interleukin 1 receptor antagonist messenger RNA, alterations in synaptic strength, and noradrenaline-dependent and persistent depressive-like and anhedonic behaviors in females. This behavioral phenotype could be potentiated inducing the lipopolysaccharide depression model. RNA sequencing and biochemical studies revealed an association with impaired microglial metabolic fitness. In conclusion, we report a clear association that links the function of the CD300f immune receptor with MDD in humans, depressive-like and anhedonic behaviors in female mice, and altered microglial metabolic reprogramming. Significance A role for innate immune receptors expressed by microglia and barrier macrophages has been postulated in neuropsychiatric diseases, including major depressive disorder (MDD). We discovered that a prevalent single-nucleotide polymorphism of the human CD300f immune receptor alters its signaling and is associated with protection against MDD in women but not in men. Interestingly, CD300f-deficient female, but not male, mice displayed depressive-like behaviors. In these mice, the absence of CD300f induced phenotypical changes of microglial cells that altered their metabolic fitness. Despite the high incidence of MDD, no effective treatments are available in many cases, and these discoveries could lead to the development of new pipelines for drugs targeting microglial cells, perivascular macrophages, and in particular the CD300f immune receptor.