PDE-4 Inhibition Rescues Aberrant Synaptic Plasticity in Drosophila and Mouse Models of Fragile X Syndrome
PDE-4 Inhibition Rescues Aberrant Synaptic Plasticity in Drosophila and Mouse Models of Fragile X Syndrome
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DOI：
10.1523/jneurosci.1356-12.2015
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发表时间：
2015-01-07
影响因子：
5.3
通讯作者：
McBride, Sean M. J.
中科院分区：
文献类型：
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作者：
Choi, Catherine H.;Schoenfeld, Brian P.;McBride, Sean M. J.
脆性X综合征（FXS）是由单一基因突变引起的智力残疾和自闭症的主要原因。以前，我们的特点是认知障碍和大脑结构缺陷的果蝇模型FXS和证明，这些障碍被救出的治疗与代谢型谷氨酸受体（mGluR）拮抗剂或锂。在苍蝇和小鼠FXS模型和FXS患者中观察到的充分记录的生化缺陷是低cAMP水平。cAMP水平可以通过mGluR信号传导来调节。在此，我们证明PDE-4抑制作为一种治疗策略，以改善记忆障碍和大脑结构缺陷的果蝇模型的脆性X。此外，我们在脆性X小鼠模型中检查了通过药物治疗抑制PDE-4的效果。我们证明，急性抑制PDE-4的药理治疗海马切片拯救增强mGluR依赖性LTD表型观察FXS小鼠。此外，我们发现FXS模型小鼠在成年期的慢性治疗也使mGluR依赖性LTD的水平恢复到野生型动物中观察到的水平。将果蝇模型的成功药物干预研究结果转化为FXS小鼠模型是一项重要进展，因为这确定并验证了PDE-4抑制作为治疗FXS患者的潜在治疗干预。
Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS.