Schafer Dorothy P, Heller Christopher T, Gunner Georgia, Heller Molly, Gordon Christopher, Hammond Timothy, Wolf Yochai, Jung Steffen, Stevens Beth
FM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States.
Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States.
Elife. 2016 Jul 26;5:e15224. doi: 10.7554/eLife.15224.
Microglia, the resident CNS macrophages, have been implicated in the pathogenesis of Rett Syndrome (RTT), an X-linked neurodevelopmental disorder. However, the mechanism by which microglia contribute to the disorder is unclear and recent data suggest that microglia do not play a causative role. Here, we use the retinogeniculate system to determine if and how microglia contribute to pathogenesis in a RTT mouse model, the Mecp2 null mouse (Mecp2(tm1.1Bird/y)). We demonstrate that microglia contribute to pathogenesis by excessively engulfing, thereby eliminating, presynaptic inputs at end stages of disease (≥P56 Mecp2 null mice) concomitant with synapse loss. Furthermore, loss or gain of Mecp2 expression specifically in microglia (Cx3cr1(CreER);Mecp2(fl/y)or Cx3cr1(Cr)(eER); Mecp2(LSL/y)) had little effect on excessive engulfment, synapse loss, or phenotypic abnormalities. Taken together, our data suggest that microglia contribute to end stages of disease by dismantling neural circuits rendered vulnerable by loss of Mecp2 in other CNS cell types.
小胶质细胞作为中枢神经系统（CNS）中的常驻巨噬细胞，已被认为与雷特综合征（RTT，一种X连锁神经发育障碍）的发病机制有关。然而，小胶质细胞导致该疾病的机制尚不清楚，并且最近的数据表明小胶质细胞并不起致病作用。在此，我们利用视网膜膝状体系统来确定小胶质细胞是否以及如何在RTT小鼠模型——Mecp2基因敲除小鼠（Mecp2(tm1.1Bird/y)）中促成疾病的发生。我们证明，在疾病晚期（≥P56的Mecp2基因敲除小鼠），小胶质细胞通过过度吞噬从而消除突触前输入，这与突触丢失同时发生，进而促成了疾病的发生。此外，特异性地在小胶质细胞中缺失或增加Mecp2表达（Cx3cr1(CreER);Mecp2(fl/y) 或Cx3cr1(Cr)(eER); Mecp2(LSL/y)）对过度吞噬、突触丢失或表型异常几乎没有影响。综上所述，我们的数据表明，小胶质细胞通过拆解因其他中枢神经系统细胞类型中Mecp2缺失而变得脆弱的神经回路，促成了疾病的晚期阶段。
