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Astroglial FMRP modulates synaptic signaling and behavior phenotypes in FXS mouse model.
Glia ( IF 6.2 ) Pub Date : 2020-09-24 , DOI: 10.1002/glia.23915
Shan-Xue Jin 1 , Haruki Higashimori 2 , Christina Schin 2 , Alessandra Tamashiro 2 , Yuqin Men 2 , Ming Sum R Chiang 2 , Rachel Jarvis 2 , Dan Cox 2 , Larry Feig 1, 3 , Yongjie Yang 2, 3
Affiliation  

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.

中文翻译:

星形胶质细胞 FMRP 调节 FXS 小鼠模型中的突触信号和行为表型。

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 蛋白的丢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 FXS 背后的以神经元为中心的分子和细胞事件已经被表征,但不同的 CNS 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是未知的。最近的证据表明,星形胶质细胞 FMRP 的选择性缺失能够调节谷氨酸摄取、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中突触信号和 FXS 相关行为和学习表型的影响cKO 和 cON 小鼠,其中 FMRP 表达在星形胶质细胞中选择性减少或恢复。我们发现星形胶质细胞 FMRP 的选择性缺失通过增强 NMDAR 介导的诱发而非自发的 miniEPSC 和延长皮质 UP 状态持续时间而导致皮质过度兴奋。星形胶质细胞 FMRP 的选择性缺失也足以增加运动机能亢进,显着降低社交新奇偏好,并诱导星形胶质细胞Fmr1 cKO 小鼠的记忆获取和消退缺陷。重要的是,星形胶质细胞 FMRP 的重新表达能够显着挽救星形胶质细胞 Fmr1 的多动症(诱发的 NMDAR 反应、UP 状态持续时间和野外试验)和社会新奇偏好控制小鼠。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 FXS 相关行为和学习表型中的深远作用,并为 FMRP 再激活策略的细胞类型考虑提供了重要的新见解。
更新日期:2020-09-24
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