Pacey Laura K K, Guan Sihui, Tharmalingam Sujeenthar, Thomsen Christian, Hampson David R
Department of Pharmaceutical Sciences Leslie Dan Faculty of Pharmacy University of Toronto 144 College Street Toronto Ontario Canada M5S 3M2.
Department of Neuroinflammation Lundbeck Research USA 215 College Road Paramus New Jersey 07652.
Brain Behav. 2015 Sep 25;5(10):e00400. doi: 10.1002/brb3.400. eCollection 2015 Oct.
Fragile X Syndrome, the most common single gene cause of autism, results from loss of the RNA-binding protein FMRP. Although FMRP is highly expressed in neurons, it has also recently been identified in glia. It has been postulated that in the absence of FMRP, abnormal function of non-neuronal cells may contribute to the pathogenesis of the disorder. We previously demonstrated reduced numbers of oligodendrocyte precursor cells and delayed myelination in the cerebellum of fragile X (Fmr1) knockout mice.
We used quantitative western blotting and immunocytochemistry to examine the status of astrocytes and microglia in the cerebellum of Fmr1 mice during development and in adulthood.
We report increased expression of the astrocyte marker GFAP in the cerebellum of Fmr1 mice starting in the second postnatal week and persisting in to adulthood. At 2 weeks postnatal, expression of Tumor Necrosis Factor Receptor 2 (TNFR2) and Leukemia Inhibitory Factor (LIF) were elevated in the Fmr1 KO cerebellum. In adults, expression of TNFR2 and the glial marker S100β were also elevated in Fmr1 knockouts, but LIF expression was not different from wild-type mice. We found no evidence of microglial activation or neuroinflammation at any age examined.
These findings demonstrate an atypical pattern of astrogliosis in the absence of microglial activation in Fmr1 knockout mouse cerebellum. Enhanced TNFR2 and LIF expression in young mice suggests that changes in the expression of astrocytic proteins may be an attempt to compensate for delayed myelination in the developing cerebellum of Fmr1 mice.
脆性X综合征是自闭症最常见的单基因病因，由RNA结合蛋白FMRP缺失所致。尽管FMRP在神经元中高度表达，但最近也在胶质细胞中被发现。据推测，在缺乏FMRP的情况下，非神经元细胞的异常功能可能导致该疾病的发病机制。我们之前证明，脆性X（Fmr1）基因敲除小鼠小脑少突胶质前体细胞数量减少且髓鞘形成延迟。
我们使用定量蛋白质免疫印迹法和免疫细胞化学法来检测Fmr1基因敲除小鼠在发育过程中和成年期小脑星形胶质细胞和小胶质细胞的状态。
我们报告称，从出生后第二周开始，Fmr1基因敲除小鼠小脑中星形胶质细胞标志物GFAP的表达增加，并持续到成年期。在出生后2周时，Fmr1基因敲除小鼠小脑中肿瘤坏死因子受体2（TNFR2）和白血病抑制因子（LIF）的表达升高。在成年期，Fmr1基因敲除小鼠中TNFR2和胶质细胞标志物S100β的表达也升高，但LIF表达与野生型小鼠无差异。在任何检测的年龄阶段，我们均未发现小胶质细胞激活或神经炎症的证据。
这些发现表明，Fmr1基因敲除小鼠小脑中在无小胶质细胞激活的情况下存在非典型的星形胶质细胞增生模式。幼鼠中TNFR2和LIF表达增强表明，星形胶质细胞蛋白表达的变化可能是为了补偿Fmr1基因敲除小鼠发育中小脑髓鞘形成延迟的一种尝试。
