TY - JOUR
T1 - CD300f immunoreceptor is associated with major depressive disorder and decreased microglial metabolic fitness
AU - Lago, Natalia
AU - Kaufmann, Fernanda N.
AU - Negro-Demontel, María Luciana
AU - Alí-Ruiz, Daniela
AU - Ghisleni, Gabriele
AU - Rego, Natalia
AU - Arcas-García, Andrea
AU - Vitureira, Nathalia
AU - Jansen, Karen
AU - Souza, Luciano M.
AU - Silva, Ricardo A.
AU - Lara, Diogo R.
AU - Pannunzio, Bruno
AU - Abin-Carriquiry, Juan Andrés
AU - Amo-Aparicio, Jesús
AU - Martin-Otal, Celia
AU - Naya, Hugo
AU - McGavern, Dorian B.
AU - Sayós, Joan
AU - López-Vales, Rubèn
AU - Kaster, Manuella P.
AU - Peluffo, Hugo
PY - 2020/3/9
Y1 - 2020/3/9
N2 - 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.
AB - 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.
KW - CD300
KW - Depression
KW - Immunereceptor
KW - Microglia
KW - RNA-seq
UR - http://www.scopus.com/inward/record.url?scp=85082330099&partnerID=8YFLogxK
U2 - 10.1073/pnas.1911816117
DO - 10.1073/pnas.1911816117
M3 - Artículo
C2 - 32152116
AN - SCOPUS:85082330099
SN - 0027-8424
VL - 117
SP - 6651
EP - 6662
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 12
ER -
