Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2014 Sep 16;21(10):543-55.
doi: 10.1101/lm.035956.114. Print 2014 Oct.

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  1 , Alexandros K Kanellopoulos  1 , Claudia Bagni  2
Affiliations
Review

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. .

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.

PubMed Disclaimer

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.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Antion MD, Merhav M, Hoeffer CA, Reis G, Kozma SC, Thomas G, Schuman EM, Rosenblum K, Klann E 2008. Removal of S6K1 and S6K2 leads to divergent alterations in learning, memory, and synaptic plasticity. Learn Mem 15: 29–38 - PMC - PubMed
    1. Bagni C, Greenough WT 2005. From mRNP trafficking to spine dysmorphogenesis: the roots of Fragile X syndrome. Nat Rev Neurosci 6: 376–387 - PubMed
    1. Bagni C, Tassone F, Neri G, Hagerman R 2012. Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics. J Clin Invest 122: 4314–4322 - PMC - PubMed
    1. Baker KB, Wray SP, Ritter R, Mason S, Lanthorn TH, Savelieva KV 2010. Male and female Fmr1 knockout mice on C57 albino background exhibit spatial learning and memory impairments. Genes Brain Behav 9: 562–574 - PubMed
    1. Banerjee P, Nayar S, Hebbar S, Fox CF, Jacobs MC, Park JH, Fernandes JJ, Dockendorff TC 2007. Substitution of critical isoleucines in the KH domains of Drosophila fragile X protein results in partial loss-of-function phenotypes. Genetics 175: 1241–1250 - PMC - PubMed

Publication types

Substances

LinkOut - more resources