Involvement of Phosphodiesterase 2A Activity in the Pathophysiology of Fragile X Syndrome
Involvement of Phosphodiesterase 2A Activity in the Pathophysiology of Fragile X Syndrome
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DOI：
10.1093/cercor/bhy192
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发表时间：
2019-08-01
期刊：
影响因子：
3.7
通讯作者：
Bardoni, Barbara
中科院分区：
文献类型：
--
作者：
Maurin, Thomas;Melancia, Francesca;Bardoni, Barbara
脆性X智力低下蛋白（FMRP）是一种RNA结合蛋白，参与mRNA的翻译调节，在突触形态和可塑性中发挥关键作用。FMRP的功能缺失导致脆性X综合征（FXS），这是遗传性智力残疾的最常见形式，也是自闭症最常见的单基因原因。没有有效的治疗方法可用于FXS。我们最近发现磷酸二酯酶2A（Pde 2a）mRNA作为FMRP的一个突出的目标。Fmr 1-KO小鼠（一种公认的FXS模型）的脑中PDE 2A酶活性增加，导致cAMP和cGMP水平降低。在这里，我们在Fmr 1-KO小鼠中抑制PDE 2A，并观察到树突棘的成熟和夸大的海马mGluR依赖性长期抑制的拯救。值得注意的是，PDE 2A阻断挽救了小鼠和大鼠Fmr 1-KO动物的社交和交流缺陷。重要的是，在新生Fmr 1-KO小鼠中对PDE 2A进行慢性抑制，随后进行洗脱期，导致在青春期小鼠中观察到的社会行为改变的挽救。总之，这些结果揭示了PDE 2A在FXS病理生理学中的关键作用，并表明其药理学抑制代表了FXS的新治疗方法。
The fragile X mental retardation protein (FMRP) is an RNA-binding protein involved in translational regulation of mRNAs that play key roles in synaptic morphology and plasticity. The functional absence of FMRP causes the fragile X syndrome (FXS), the most common form of inherited intellectual disability and the most common monogenic cause of autism. No effective treatment is available for FXS. We recently identified the Phosphodiesterase 2A (Pde2a) mRNA as a prominent target of FMRP. PDE2A enzymatic activity is increased in the brain of Fmr1-KO mice, a recognized model of FXS, leading to decreased levels of cAMP and cGMP. Here, we pharmacologically inhibited PDE2A in Fmr1-KO mice and observed a rescue both of the maturity of dendritic spines and of the exaggerated hippocampal mGluR-dependent long-term depression. Remarkably, PDE2A blockade rescued the social and communicative deficits of both mouse and rat Fmr1-KO animals. Importantly, chronic inhibition of PDE2A in newborn Fmr1-KO mice followed by a washout interval, resulted in the rescue of the altered social behavior observed in adolescent mice. Altogether, these results reveal the key role of PDE2A in the physiopathology of FXS and suggest that its pharmacological inhibition represents a novel therapeutic approach for FXS.