Treatment with glutamate receptor antagonists or lithium reverses behavioral defects, memory failure, and neuroanatomical abnormalities in a Drosophila model of Fragile X syndrome, the most common form of inherited mental retardation in humans. Reported in the March 3 Neuron, the results bolster the emerging hypothesis that overactive signaling by some metabotropic glutamate receptors (mGluRs) underlies the pathology of Fragile X, and they open up a possible new avenue for treating Fragile X symptoms in humans. The authors are a collaborative team led by Thomas Jongens at University of Pennsylvania School of Medicine in Philadelphia.

The genetic lesion in Fragile X mental retardation has been known for more than a decade to be fmr-1, a gene encoding an RNA-binding protein that functions to suppress translation. But it was not known how a null mutation in fmr-1 could cause a complex phenotype including progressive cognitive impairment and memory deficits. Only recently have studies of synaptic plasticity in fmr-1 knockout mice led to the proposal that loss of the fmr protein deregulates protein synthesis in response to mGluR activation (Huber et al., 2002). The resulting exaggerated response to glutamate causes synaptic changes that produce the diverse symptoms of Fragile X, according to the theory (Bear et al., 2004).

To put this hypothesis to the test, first author Sean McBride and colleagues turned to a Drosophila model of Fragile X, the dfmr-1 gene knockout. The mutant flies had previously been shown to display abnormal courtship behavior—male flies make a lackadaisical approach to willing virgin females, and they exhibit fewer courting and mating behaviors in a given time than do their wild-type peers. When the knockout flies were fed the mGluR antagonist MPEP, they perked up and displayed normal courtship behavior.

The researchers were able to test the mutant flies’ learning and memory for the first time using a courtship conditioning assay. In this protocol, exposure to a non-receptive female will cause a progressive decrease in mating behaviors in the male (the learning stage), and this decrease is exhibited for several hours even toward a new, receptive female (the memory stage). The researchers demonstrated that knockout flies had no trouble learning to avoid non-receptive females, but failed completely at the memory phase of the test. Feeding the flies MPEP restored their memory function.

To prove that the Drosophila mGluR was mediating the observed responses, the researchers tested three additional receptor antagonists as well as lithium, which blocks mGluR activation of inositol phosphate production and calcium release. All the agents had similar beneficial effects on learning and memory in the mutants.

The authors further report that treatment of adult flies improved cognitive and memory function, but starting the compounds in the larval stage had the greatest benefit. Only when treatment started during larval development did neuroanatomical defects that typically occur in the mushroom bodies of mutant flies revert to normal. Interestingly, however, this normalization of a brain structure did not seem to be required for improvement of the cognitive and memory defects.

Of course, the jump from feeding flies to treating humans can be a difficult one. Even so, the Drosophila results fit with observations of mGluR activity in Fragile X mice, according to an accompanying commentary by Gül Dölen and Mark Bear at the Massachusetts Institute of Technology, who conclude that “the current study provides a compelling demonstration that pharmacotherapy has the potential to cure aspects of Fragile X.”

The finding that mGluR blockade can restore synaptic plasticity in Fragile X mutants will surely have researchers checking out the role of these receptors in Alzheimer disease, where synaptic dysfunction and loss is an early event in disease progression. And the new information on lithium’s effects in Fragile X only adds to the interest in this familiar drug, which is already being studied for its ability to inhibit GSK3 and production of Aβ peptide (see ARF related news story).—Pat McCaffrey

Pat McCaffrey is a freelance science writer in Newton, Massachusetts.


  1. Fragile X mental retardation syndrome (FXS), the most common form of inheritable retardation, results from a trinucleotide repeat expansion in the FMR1 gene, which ultimately results in transcriptional silencing of the Fragile X mental retardation protein (FMRP). Recent research has made great strides in understanding the function of FMRP and this has shed light on the molecular mechanisms of the cognitive deficits observed in FXS (O'Donnell and Warren, 2002).

    FMRP knockout mice exhibit many symptoms similar to human patients, including dendritic spine abnormalities and cognitive dysfunction. Deficits in synaptic plasticity have also been observed in knockout mice, including enhancement of long-term depression (LTD) in the hippocampus. FMRP is an RNA binding protein that has been shown to bind selective mRNAs in dendrites. Indeed, many neuronal mRNAs localize to dendrites where they undergo local translation. FMRP has been shown to both transport and regulate translation of these specific mRNAs, many of which include important synaptic proteins such as MAP1, CaMKII and Arc (Zalfa et al., 2003). In tandem with these findings, overactivation of group 1 metabotropic glutamate receptor (mGluR) signaling has been shown to mimic certain Fragile X symptoms, leading to the mGluR theory (recently reviewed in Bear et al., 2004) that posits a leading role for mGluR signaling in FXS. A form of LTD requires mGluR activation and is dependent on protein synthesis, linking mGluR signaling to FMRP-dependent protein synthesis (Huber et al., 2000).

    A Drosophila model of Fragile X has been developed by knocking out the Drosophila FMRP homologue dfmr1. Studies of these flies have uncovered neuronal and behavioral phenotypes with parallels to symptoms observed in FXS patients, including alterations in circadian rhythms and synaptic branching. This paper uses this model to show that mGluR antagonists can treat behavioral deficits.

    The authors utilized courtship mating to address whether dfmr1 knockout exhibited deficits in learning and memory. Courtship behavior in Drosophila is innate and involves a complex set of behaviors in order for copulation to occur. The authors find that dfmr1 KO flies learn normally but are deficient in retaining memory in two paradigms of courtship behavior. Surprisingly, when the authors fed the KO flies MPEP (a selective mGluR5 antagonist in mammals), these deficits were reversed. This is surprising because the only known Drosophila mGluR (dmGluRA) is most similar to group II mammalian mGluRs and shows little homology to mGLuR5, a group 1 mGluR. Three other mGluR antagonists were used and exhibited similar beneficial effects in the KO flies.

    Feeding flies MPEP during and after development had similar beneficial effects, although restoration was greatest in developmentally fed flies. Intriguingly, mGluR antagonists fed during development also restored an anatomical deficit in the mushroom bodies of KO flies. Mushroom bodies are brain structures that are thought to be equivalent to the hippocampus in vertebrates. However, MPEP fed post-development did not restore the anatomical deficits, suggesting that the anatomical abnormality is not responsible for the memory deficits.

    Although the findings from this study provide suggestive evidence that the mGluR theory of Fragile X applies across species, further work will be needed to verify this. The signaling pathways downstream of dmGlurA are unclear, and it will be interesting to determine if FMRP-dependent protein synthesis is also controlled by dmGluRA. A limitation of this paper is that the authors do not definitively show that the mGluR antagonists are indeed acting directly on the dmGluRA receptor. Genetically reducing dmGluRA in flies will be needed to verify that the observed benefits of the drugs are acting through dmGluRA. However, the study does suggest that pharmacotherapy may be a viable treatment for FXS and is a promising step forward in alleviating the burden of this disease.


    . The mGluR theory of fragile X mental retardation. Trends Neurosci. 2004 Jul;27(7):370-7. PubMed.

    . Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science. 2000 May 19;288(5469):1254-7. PubMed.

    . A decade of molecular studies of fragile X syndrome. Annu Rev Neurosci. 2002;25:315-38. PubMed.

    . The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses. Cell. 2003 Feb 7;112(3):317-27. PubMed.

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News Citations

  1. Lithium Hinders Aβ Generation, Buffing Up GSK as Drug Target

Paper Citations

  1. . Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc Natl Acad Sci U S A. 2002 May 28;99(11):7746-50. PubMed.
  2. . The mGluR theory of fragile X mental retardation. Trends Neurosci. 2004 Jul;27(7):370-7. PubMed.

Further Reading

Primary Papers

  1. . Pharmacological rescue of synaptic plasticity, courtship behavior, and mushroom body defects in a Drosophila model of fragile X syndrome. Neuron. 2005 Mar 3;45(5):753-64. PubMed.
  2. . Courting a cure for fragile X. Neuron. 2005 Mar 3;45(5):642-4. PubMed.