Dölen G, Bear MF.
Courting a cure for fragile X.
Neuron. 2005 Mar 3;45(5):642-4.
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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.
Bear MF, Huber KM, Warren ST.
The mGluR theory of fragile X mental retardation.
Trends Neurosci. 2004 Jul;27(7):370-7.
Huber KM, Kayser MS, Bear MF.
Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression.
Science. 2000 May 19;288(5469):1254-7.
O'Donnell WT, Warren ST.
A decade of molecular studies of fragile X syndrome.
Annu Rev Neurosci. 2002;25:315-38.
Zalfa F, Giorgi M, Primerano B, Moro A, Di Penta A, Reis S, Oostra B, Bagni C.
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.