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Neurofibromatosis 1 - Mutant microglia exhibit sexually-dimorphic cyclic AMP-dependent purinergic defects
Nirmeen Elmadany1, Francesca Logiacco1, Alice Buonfiglioli2
1Cellular Neurosciences, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany; Department of Biology, Chemistry, and Pharmacy, Freie Universität Berlin, 12169 Berlin, Germany.
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.
Insights
Sex-specific defects in microglia function were observed in a mouse model of Neurofibromatosis type 1 (NF1). Male NF1 mice showed impaired purinergic signaling and reduced microglial process motility, linked to cyclic AMP dysregulation.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia are crucial for brain homeostasis and are influenced by sex and genetic factors.
- Neurofibromatosis type 1 (NF1) is a genetic disorder with known sex-specific differences.
- NF1 influences microglia function, impacting brain health.
Purpose of the Study:
- To investigate the impact of sex and NF1 mutation on microglia biology.
- To elucidate the mechanisms underlying sex-by-genotype interactions in microglia.
Main Methods:
- Utilized genetically engineered mice modeling Neurofibromatosis type 1 (Nf1+/- mice).
- Assessed microglia phagocytic activity, purinergic signaling (ATP-induced currents), and process motility (laser-induced lesion).
- Analyzed cyclic AMP regulation and purinergic receptor expression.
Main Results:
- Reduced phagocytic activity in both male and female Nf1+/- mice.
- Impaired purinergic control of phagocytosis, P2Y-mediated currents, and process motility exclusively in male Nf1+/- mice.
- Male Nf1+/- microglia defects were linked to cyclic AMP dysregulation, not receptor expression changes.
Conclusions:
- Established a significant sex-by-genotype interaction affecting microglia function in the adult mouse brain.
- Identified male-specific defects in cyclic AMP regulation as the cause of impaired microglia function in NF1 mice.
- Demonstrated that phosphodiesterase blockade can restore normal microglia function in affected male mice.
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