Astrocytic Contributions to Synaptic and Learning Abnormalities in a Mouse Model of Fragile X Syndrome.
Astrocytic Contributions to Synaptic and Learning Abnormalities in a Mouse Model of Fragile X Syndrome.
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DOI：
10.1016/j.biopsych.2016.08.036
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发表时间：
2017-07-15
影响因子：
10.6
通讯作者：
Zuo Y
中科院分区：
文献类型：
--
作者：
Hodges JL;Yu X;Gilmore A;Bennett H;Tjia M;Perna JF;Chen CC;Li X;Lu J;Zuo Y
脆性 X 综合征 (FXS) 是由单基因突变引起的最常见的精神发育迟滞类型。它是由 FMR1 基因沉默及其蛋白质产物脆性 X 智力迟钝蛋白 (FMRP) 的损失引起的。 Fmr1 全基因敲除 (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系统疾病的重要促成因素。本研究调查了星形胶质细胞对 FXS 相关突触异常和学习障碍进展的影响。利用 Cre-lox 系统，我们生成并表征了 FMRP 被选择性删除或仅在星形胶质细胞中表达的小鼠。我们进行了体内双光子成像，以跟踪运动皮层神经元树突的脊柱动力学/形态，并检查相关的行为缺陷。我们发现，成年星形胶质细胞特异性 Fmr1 KO 小鼠的运动皮层棘密度增加，运动技能学习受损。学习缺陷与运动皮层中缺乏增强的脊柱动力学同时发生，而运动皮层通常是对运动技能习得做出反应而发生的。虽然星形胶质细胞特异性 Fmr1 KO 小鼠的脊柱密度在一个月龄时正常，但新脊柱的形成速度较高。此外，仅在星形胶质细胞中表达 FMRP 不足以挽救大多数脊柱或行为缺陷。我们的工作表明星形细胞-神经元对 FXS 发病机制有共同作用，并揭示了青春期脊柱形成的增强先于成年 Fmr1 KO 小鼠中发现的脊柱过多和行为缺陷。
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 (FMRP). Fmr1 global knock out (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 FMRP 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 an 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. While spine density was normal at one month of age in astrocyte-specific Fmr1 KO mice, new spines formed at an elevated rate. Furthermore, expression of FMRP only in 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.