Research ArticleFragile X Syndrome

Sustained correction of associative learning deficits after brief, early treatment in a rat model of Fragile X Syndrome

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Science Translational Medicine  29 May 2019:
Vol. 11, Issue 494, eaao0498
DOI: 10.1126/scitranslmed.aao0498

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Optimizing therapeutic intervention for Fragile X Syndrome

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene. Pharmacological intervention using the cholesterol-lowering drug lovastatin had therapeutic effect on behavior in patients. Selecting the time of intervention and the therapeutic protocol is critical for maximizing the therapeutic effects. Now, Asiminas et al. tested the effect of temporary early treatment with lovastatin in a rat model of FXS. The authors showed that 5-week treatment initiated before complete development of cognitive abilities rescued cognitive development. The therapeutic effect persisted for more than 3 months after treatment termination. The results suggest that lovastatin treatment initiated early during development might have disease-modifying effect in FXS.


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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