Jin Shan-Xue, Higashimori Haruki, Schin Christina, Tamashiro Alessandra, Men Yuqin, Chiang Ming Sum R, Jarvis Rachel, Cox Dan, Feig Larry, Yang Yongjie
Department of Developmental, Molecular, and Cellular Biology, Tufts University, Boston, Massachusetts, USA.
Department of Neuroscience, School of Medicine, Tufts University, Boston, Massachusetts, USA.
Glia. 2021 Mar;69(3):594-608. doi: 10.1002/glia.23915. Epub 2020 Sep 24.
Fragile X syndrome (FXS) is one of the most common inherited intellectual disability (ID) disorders, in which the loss of FMRP protein induces a range of cellular signaling changes primarily through excess protein synthesis. Although neuron-centered molecular and cellular events underlying FXS have been characterized, how different CNS cell types are involved in typical FXS synaptic signaling changes and behavioral phenotypes is largely unknown. Recent evidence suggests that selective loss of astroglial FMRP is able to dysregulate glutamate uptake, increase spine density, and impair motor-skill learning. Here we investigated the effect of astroglial FMRP on synaptic signaling and FXS-related behavioral and learning phenotypes in astroglial Fmr1 cKO and cON mice in which FMRP expression is selectively diminished or restored in astroglia. We found that selective loss of astroglial FMRP contributes to cortical hyperexcitability by enhancing NMDAR-mediated evoked but not spontaneous miniEPSCs and elongating cortical UP state duration. Selective loss of astroglial FMRP is also sufficient to increase locomotor hyperactivity, significantly diminish social novelty preference, and induce memory acquisition and extinction deficits in astroglial Fmr1 cKO mice. Importantly, re-expression of astroglial FMRP is able to significantly rescue the hyperactivity (evoked NMDAR response, UP state duration, and open field test) and social novelty preference in astroglial Fmr1 cON mice. These results demonstrate a profound role of astroglial FMRP in the evoked synaptic signaling, spontaneously occurring cortical UP states, and FXS-related behavioral and learning phenotypes and provide important new insights in the cell type consideration for the FMRP reactivation strategy.
脆性X综合征（FXS）是最常见的遗传性智力障碍（ID）疾病之一，其中FMRP蛋白的缺失主要通过过量的蛋白质合成诱导一系列细胞信号变化。尽管已经对FXS潜在的以神经元为中心的分子和细胞事件进行了表征，但不同的中枢神经系统细胞类型如何参与典型的FXS突触信号变化和行为表型在很大程度上尚不清楚。最近的证据表明，星形胶质细胞FMRP的选择性缺失能够失调谷氨酸摄取、增加脊柱密度并损害运动技能学习。在这里，我们研究了星形胶质细胞FMRP对星形胶质细胞Fmr1 cKO和cON小鼠的突触信号以及与FXS相关的行为和学习表型的影响，在这些小鼠中，FMRP表达在星形胶质细胞中被选择性降低或恢复。我们发现，星形胶质细胞FMRP的选择性缺失通过增强NMDAR介导的诱发微小兴奋性突触后电流（miniEPSCs）而非自发微小兴奋性突触后电流，并延长皮质UP状态持续时间，导致皮质兴奋性过高。星形胶质细胞FMRP的选择性缺失也足以增加运动活动亢进、显著降低对新事物的偏好，并在星形胶质细胞Fmr1 cKO小鼠中诱导记忆获取和消退缺陷。重要的是，星形胶质细胞FMRP的重新表达能够显著挽救星形胶质细胞Fmr1 cON小鼠的多动（诱发的NMDAR反应、UP状态持续时间和旷场试验）和对新事物的偏好。这些结果证明了星形胶质细胞FMRP在诱发的突触信号、自发发生的皮质UP状态以及与FXS相关的行为和学习表型中具有重要作用，并为FMRP重新激活策略的细胞类型考虑提供了重要的新见解。
