Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA.
The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen 518055, China.
Biol Psychiatry. 2017 Jul 15;82(2):139-149. doi: 10.1016/j.biopsych.2016.08.036. Epub 2016 Sep 13.
Fragile X syndrome (FXS) is the most common type of mental retardation attributable to a single-gene mutation. It is caused by FMR1 gene silencing and the consequent loss of its protein product, fragile X mental retardation protein. Fmr1 global knockout (KO) mice recapitulate many behavioral and synaptic phenotypes associated with FXS. Abundant evidence suggests that astrocytes are important contributors to neurological diseases. This study investigates astrocytic contributions to the progression of synaptic abnormalities and learning impairments associated with FXS.
Taking advantage of the Cre-lox system, we generated and characterized mice in which fragile X mental retardation protein is selectively deleted or exclusively expressed in astrocytes. We performed in vivo two-photon imaging to track spine dynamics/morphology along dendrites of neurons in the motor cortex and examined associated behavioral defects.
We found that adult astrocyte-specific Fmr1 KO mice displayed increased spine density in the motor cortex and impaired motor-skill learning. The learning defect coincided with a lack of enhanced spine dynamics in the motor cortex that normally occurs in response to motor skill acquisition. Although spine density was normal at 1 month of age in astrocyte-specific Fmr1 KO mice, new spines formed at an elevated rate. Furthermore, fragile X mental retardation protein expression in only astrocytes was insufficient to rescue most spine or behavioral defects.
Our work suggests a joint astrocytic-neuronal contribution to FXS pathogenesis and reveals that heightened spine formation during adolescence precedes the overabundance of spines and behavioral defects found in adult Fmr1 KO mice.
脆性 X 综合征（FXS）是最常见的智力障碍类型，可归因于单一基因突变。它是由 FMR1 基因沉默和随之而来的其蛋白产物脆性 X 智力迟钝蛋白的缺失引起的。Fmr1 全局敲除（KO）小鼠重现了许多与 FXS 相关的行为和突触表型。大量证据表明，星形胶质细胞是神经疾病的重要贡献者。本研究调查了星形胶质细胞对与 FXS 相关的突触异常和学习障碍进展的贡献。
利用 Cre-lox 系统，我们生成并表征了选择性在星形胶质细胞中缺失或特异性表达脆性 X 智力迟钝蛋白的小鼠。我们进行了体内双光子成像，以跟踪运动皮层神经元树突上的棘突动态/形态，并检查了相关的行为缺陷。
我们发现，成年星形胶质细胞特异性 Fmr1 KO 小鼠的运动皮层棘突密度增加，运动技能学习受损。学习缺陷与运动皮层中通常在获得运动技能时发生的棘突动态增强缺乏一致。尽管在星形胶质细胞特异性 Fmr1 KO 小鼠中，1 月龄时棘突密度正常，但新形成的棘突以较高的速度形成。此外，仅在星形胶质细胞中表达脆性 X 智力迟钝蛋白不足以挽救大多数棘突或行为缺陷。
我们的工作表明星形胶质细胞和神经元共同参与 FXS 的发病机制，并表明青春期棘突形成增加先于成年 Fmr1 KO 小鼠中发现的棘突过多和行为缺陷。
