Neurofibromatosis 1-Mutant microglia exhibit sexually-dimorphic cyclic AMP-dependent purinergic defects

NEUROBIOLOGY OF DISEASE

卷:144

Article

Elmadany, Nirmeen^1,7  Logiacco, Francesca^1,7  Buonfiglioli, Alice^1,3,4,5,6  Haage, Verena C.¹  Wright-Jin, Elizabeth C.²  Schattenberg, Alexander¹  Papawassiliou, Roxane M.¹  Kettenmann, Helmut¹  Semtner, Marcus¹  Gutmann, David H.^1,2 

[1] Max Delbruck Ctr Mol Med, Cellular Neurosci, Helmholtz Assoc, D-13125 Berlin, Germany

[2] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA

[3] Charite Univ Med Berlin, Inst Cell Biol & Neurobiol, D-10117 Berlin, Germany

[4] Free Univ Berlin, D-10117 Berlin, Germany

[5] Humboldt Univ, D-10117 Berlin, Germany

[6] Berlin Inst Hlth, D-10117 Berlin, Germany

[7] Free Univ Berlin, Dept Biol Chem & Pharm, D-12169 Berlin, Germany

关键词: Brain;    Neurofibromin;    P2RY12;    Purinergic signaling;    Sex differences;    Microglia;    cAMP;   

DOI  :  10.1016/j.nbd.2020.105030

来源: Elsevier

【 摘 要 】

As critical regulators of brain homeostasis, microglia are influenced by numerous factors, including sex and genetic mutations. To study the impact of these factors on microglia biology, we employed genetically engineered mice that model Neurofibromatosis type 1 (NF1), a disorder characterized by clinically relevant sexually dimorphic differences. While microglia phagocytic activity was reduced in both male and female heterozygous Nf1 mutant (Nf1+/-) mice, purinergic control of phagocytosis was only affected in male Nf1+/-mice. ATP-induced P2Y-mediated membrane currents and P2RY12-dependent laser lesion-induced accumulation of microglial processes were also only impaired in male, but not female Nf1+/-, microglia. These defects resulted from Nf1+/- male-specific defects in cyclic AMP regulation, rather than from changes in purinergic receptor expression. Cyclic AMP elevation by phosphodiesterase blockade restored the male Nf1+/- microglia defects in P2Y-dependent membrane currents and process motility. Taken together, these data establish a sex-bygenotype interaction important to microglia function in the adult mouse brain.