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Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us - PubMed

  • ️Wed Jan 01 2014

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Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

Ana Rita Santos et al. Learn Mem. 2014.

Abstract

The Fragile X syndrome (FXS) is the most frequent form of inherited mental disability and is considered a monogenic cause of autism spectrum disorder. FXS is caused by a triplet expansion that inhibits the expression of the FMR1 gene. The gene product, the Fragile X Mental Retardation Protein (FMRP), regulates mRNA metabolism in brain and nonneuronal cells. During brain development, FMRP controls the expression of key molecules involved in receptor signaling, cytoskeleton remodeling, protein synthesis and, ultimately, spine morphology. Symptoms associated with FXS include neurodevelopmental delay, cognitive impairment, anxiety, hyperactivity, and autistic-like behavior. Twenty years ago the first Fmr1 KO mouse to study FXS was generated, and several years later other key models including the mutant Drosophila melanogaster, dFmr1, have further helped the understanding of the cellular and molecular causes behind this complex syndrome. Here, we review to which extent these biological models are affected by the absence of FMRP, pointing out the similarities with the observed human dysfunction. Additionally, we discuss several potential treatments under study in animal models that are able to partially revert some of the FXS abnormalities.

© 2014 Santos et al.; Published by Cold Spring Harbor Laboratory Press.

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Figures

Figure 1.
Figure 1.

Molecular signaling altered in Fragile X syndrome. In the absence of FMRP protein translation is enhanced and several proteins encoded by FMRP targets such as APP, STEP, MAP1B, ARC, CaMKIIα, and others are up-regulated. In addition, many receptors are deregulated in FXS. Therefore, to normalize the observed behavioral phenotypes, several drugs have been used—in fly, animal models, and affected patients—to correct or revert some of the abnormalities. Among them: mGluR5 antagonists (MPEP, Fenobam, AFQ056, STX107, Acamprosate, RO491752, CTEP, LY341495, MPPG, and MTPG), agonists of the GABAergic pathway (Asbaclofen, Ganaxolene, and Acamprosate) and AMPAR signaling (CX516), antagonist of the cholinergic pathway (Donepezil), among others. Studies using fly and animal models have shown that targeting specific molecules/pathways corrected some defects and this information may be used to develop nontoxic drugs (denoted by the dashed line), such as ERK, PAK, and PKC inhibitors.

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