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

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Item Type:Article
Title:Neurofibromatosis 1 - mutant microglia exhibit sexually-dimorphic cyclic AMP-dependent purinergic defects
Creators Name:Elmadany, N. and Logiacco, F. and Buonfiglioli, A. and Haage, V. and Wright-Jin, E.C. and Schattenberg, A. and Papawassiliou, R. and Kettenmann, H. and Semtner, M. and Gutmann, D.H.
Abstract: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-by-genotype interaction important to microglia function in the adult mouse brain.
Keywords:Brain, Neurofibromin, P2RY12, Purinergic Signaling, Sex Differences, Microglia, Animals, Mice
Source:Neurobiology of Disease
Page Range:105030
Date:October 2020
Official Publication:https://doi.org/10.1016/j.nbd.2020.105030
PubMed:View item in PubMed

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