Sustained correction of associative learning deficits after brief, early treatment in a rat model of Fragile X Syndrome.
Sustained correction of associative learning deficits after brief, early treatment in a rat model of Fragile X Syndrome.
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DOI：
10.1126/scitranslmed.aao0498
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发表时间：
2019-05-29
影响因子：
17.1
通讯作者：
Kind PC
中科院分区：
文献类型：
--
作者：
Asiminas A;Jackson AD;Louros SR;Till SM;Spano T;Dando O;Bear MF;Chattarji S;Hardingham GE;Osterweil EK;Wyllie DJA;Wood ER;Kind PC
脆性X综合征（FXS）是自闭症和智力残疾最常见的单基因形式之一。动物模型的临床前研究突出了药物干预策略缓解FXS症状的潜力。然而，治疗策略是否可以根据定义特定表型出现的发育时间窗进行调整尚不清楚。同样，即使在治疗停止后，短暂的早期干预是否能产生持久的有益影响也是未知的。为了解决这些问题，我们首先研究了在FXS大鼠模型中获得联想学习的发育概况。联想记忆是使用一系列依赖于动物探索新奇事物的先天倾向的行为范式进行测试的。Fmr1基因敲除（KO）大鼠在获得物体位置识别方面表现出发育延迟，并且在任何测试年龄（最多23周龄）都没有表现出物体位置上下文识别范式。在建立这种联想记忆能力的正常发育期内，用洛伐他汀治疗5至9周龄的Fmr1 KO大鼠，可防止缺陷的出现，但对野生型动物无影响。此外，我们在治疗后的几个月内没有观察到FXS大鼠的认知表现的退化。这种认知功能正常发育轨迹的恢复与突触可塑性和蛋白质合成改变的持续拯救有关。这些发现提供了概念证据，即神经发育障碍中认知功能受损的出现可以通过简短的早期药物干预来预防。
Fragile X Syndrome (FXS) is one of the most common monogenic forms of autism and intellectual disability. Preclinical studies in animal models have highlighted the potential of pharmaceutical intervention strategies for alleviating the symptoms of FXS. However, whether treatment strategies can be tailored to developmental time windows that define the emergence of particular phenotypes is unknown. Similarly, whether a brief, early intervention can have long-lasting beneficial effects, even after treatment cessation, is also unknown. To address these questions, we first examined the developmental profile for the acquisition of associative learning in a rat model of FXS. Associative memory was tested using a range of behavioral paradigms that rely on an animal’s innate tendency to explore novelty. Fmr1 knockout (KO) rats showed a developmental delay in their acquisition of object-place recognition and did not demonstrate object-place-context recognition paradigm at any age tested (up to 23 weeks of age). Treatment of Fmr1 KO rats with lovastatin between 5 and 9 weeks of age, during the normal developmental period that this associative memory capability is established, prevents the emergence of deficits but has no effect in wild-type animals. Moreover, we observe no regression of cognitive performance in the FXS rats over several months after treatment. This restoration of the normal developmental trajectory of cognitive function is associated with the sustained rescue of both synaptic plasticity and altered protein synthesis. The findings provide proof of concept that the impaired emergence of the cognitive repertoire in neurodevelopmental disorders may be prevented by brief, early pharmacological intervention.
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影响因子：
2.7
作者：
Dix, SL;Aggleton, JP
通讯作者：
Aggleton, JP
影响因子：
2.7
作者：
ENNACEUR, A;DELACOUR, J
通讯作者：
DELACOUR, J
影响因子：
81.5
作者：
Hagerman, Randi J.;Berry-Kravis, Elizabeth;Hagerman, Paul J.
通讯作者：
Hagerman, Paul J.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
5.3
作者：
Eacott, MJ;Norman, G
通讯作者：
Norman, G