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.
- Huber KM, Gallagher SM, Warren ST, Bear MF. 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.
- Bear MF, Huber KM, Warren ST. The mGluR theory of fragile X mental retardation. Trends Neurosci. 2004 Jul;27(7):370-7. PubMed.
- McBride SM, Choi CH, Wang Y, Liebelt D, Braunstein E, Ferreiro D, Sehgal A, Siwicki KK, Dockendorff TC, Nguyen HT, McDonald TV, Jongens TA. 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.
- Dölen G, Bear MF. Courting a cure for fragile X. Neuron. 2005 Mar 3;45(5):642-4. PubMed.