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CD300f immunoreceptor is associated with major depressive disorder and decreased microglial metabolic fitness
Natalia Lago1, Fernanda N Kaufmann2, María Luciana Negro-Demontel1,3
1Neuroinflammation and Gene Therapy Laboratory, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay.
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.
Insights
The CD300f immune receptor plays a role in major depressive disorder (MDD). A specific genetic variant protects against MDD, while its absence in mice causes depression-like behaviors and altered microglial metabolism.
Area of Science:
- Neuroimmunology
- Psychiatry
- Genetics
Background:
- Microglia, the immune cells of the brain, are increasingly implicated in neuropsychiatric disorders like major depressive disorder (MDD).
- Immune receptors on microglia are key regulators of their function in neurological conditions.
- The CD300f immune receptor's role in microglial regulation and its link to MDD requires further investigation.
Purpose of the Study:
- To investigate the role of the CD300f immune receptor in regulating microglial phenotype.
- To explore the contribution of CD300f to major depressive disorder (MDD) using preclinical and clinical evidence.
Main Methods:
- Analysis of a common CD300f single-nucleotide polymorphism (rs2034310) in human subjects.
- Phenotypic characterization of CD300f knockout (CD300f-/-) mice, including behavioral tests and molecular analyses.
- Induction of a lipopolysaccharide depression model in mice.
- RNA sequencing and biochemical assays to assess microglial metabolic fitness.
Main Results:
- A prevalent CD300f polymorphism (rs2034310) is associated with protection against MDD, particularly in women.
- CD300f-/- mice exhibited MDD-relevant traits: increased microglia, elevated inflammatory markers (IL-6, IL-1RA), synaptic alterations, and depressive-like behaviors in females.
- These behaviors were exacerbated by a lipopolysaccharide-induced depression model.
- Impaired microglial metabolic fitness was identified through RNA sequencing and biochemical studies.
Conclusions:
- The CD300f immune receptor is functionally linked to major depressive disorder (MDD) in humans.
- CD300f deficiency in mice recapitulates key aspects of MDD, including behavioral deficits and altered microglial metabolism, especially in females.
- These findings highlight CD300f as a potential therapeutic target for MDD, particularly concerning microglial function and metabolic reprogramming.
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