Cellular 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.
Cellular Neurosciences, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany; Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
Neurobiol Dis. 2020 Oct;144:105030. doi: 10.1016/j.nbd.2020.105030. Epub 2020 Jul 29.
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.
作为大脑内稳态的关键调节者，小胶质细胞受许多因素影响，包括性别和基因突变。为了研究这些因素对小胶质细胞生物学的影响，我们使用了基因工程小鼠来模拟神经纤维瘤病 1 型（NF1），这是一种具有临床相关性别二态性差异的疾病。虽然雄性和雌性杂合子 Nf1 突变（Nf1+/-）小鼠的小胶质细胞吞噬活性均降低，但只有雄性 Nf1+/-小鼠的吞噬作用受到嘌呤能控制的影响。ATP 诱导的 P2Y 介导的膜电流和 P2RY12 依赖性激光损伤诱导的小胶质细胞突起积累也仅在雄性而非雌性 Nf1+/-小胶质细胞中受到损害。这些缺陷是由于 Nf1+/-雄性特有的环磷酸腺苷调节缺陷所致，而不是由于嘌呤能受体表达的变化。通过磷酸二酯酶阻断升高环磷酸腺苷可恢复雄性 Nf1+/-小胶质细胞在 P2Y 依赖性膜电流和突起运动中的缺陷。总之，这些数据确立了一种性别与基因型相互作用，对成年小鼠大脑中小胶质细胞功能很重要。
