21 December 2007. Fragile X syndrome, arising from the silencing of the FMR1 gene, is the most common cause of inherited mental retardation and a leading cause of autism. The synaptic dysfunctions seen in Fragile X are proposed to stem from overactivation of metabotropic glutamate receptors (mGluRs) as a result of the loss of counterbalancing fmr-1 protein activity (Bear et al., 2004). This idea, called the mGluR theory of Fragile X mental retardation, has held up in flies, where pharmacological inhibition of mGluRs reverses the effects of fmr-1 loss (see ARF related news story). Now, Mark Bear and colleagues at MIT have provided definitive evidence for the same counterbalancing act in mice. Their study in the December 20 Neuron shows that a 50 percent reduction in mGluR5 activity can reverse many of the phenotypes associated with the Fragile X mutation. The work suggests that partial pharmacological inhibition of mGluR5 activity might provide a way to ameliorate currently untreatable Fragile X retardation and some forms of autism.
To test the role of mGluR activation in Fragile X, lead author Gul Dolen, a graduate student at Brown Medical School in Providence, Rhode Island, crossed two knockout mouse lines to create fmr-1 mutant mice with a half-dose of the mouse homolog of mGluR5 (Grm5), the major group 1 mGluR in the forebrain. The investigators concentrated on the mGluR5 heterozygote knockouts as a way of testing the effect of partial receptor blockage, a more likely clinical scenario than full blockage.
The investigators first established that reducing GluR5 by half reduced synaptic long-term depression (LTD), a known pathological effect of fmr-1 knockout. From there, they went on to assess a long list of other phenotypes that this mouse model shares with the human disorder. Among them, they found that reducing mGluR5 activity corrected defects in experience-dependent synaptic plasticity, normalized protein synthesis in the hippocampus, reduced dendritic spine density, restored hippocampal-dependent memory, and reversed seizure disorders in the mice. Non-neuronal phenotypes also improved; for example, the scientists noted a slowdown of the accelerated body growth that occurs in young fmr-1 knockouts.
“It is remarkable that by reducing mGluR5 gene dosage by 50 percent, we were able to bring multiple, widely varied Fragile X phenotypes significantly closer to normal,” the authors write. Not all the fmr-1 phenotypes were reversed, however, as the mice retained an abnormal testicular growth.
“A simple way to conceptualize the constellation of findings is that Fragile X is a disorder of excess—excessive sensitivity to environmental change, synaptic connectivity, protein synthesis, memory extinct, body growth, and excitability—and these excesses can be corrected by reducing mGluR5,” the authors conclude.
The therapeutic implications are clear, and on that front Bear has founded a company to pursue the commercialization of mGluR5 antagonists for treating Fragile X syndrome and autism. According to information on its website, the company has licensed compounds from Merck and is in preclinical development of one selective mGluR antagonist. With positive animal model data in hand, the company says that provided the safety profile is acceptable, it hopes to initiate human studies with the compound in 2008. A critical outstanding question remains as to what extent the effects of the Fragile X mutation are reversible in mature neurons, and which effects lock in during development.
The study calls to mind recent work on AD from Lennart Mucke and colleagues, where knocking out tau expression ameliorated previously established Aβ-related phenotypes in an amyloid precursor protein transgenic mouse model of AD (see ARF related news story). That report, among others, is helping to fuel a new interest in tau as a therapeutic target in AD. The approach of knocking down putative downstream effectors to known genetic lesions is turning out to be a fruitful path both for illuminating the pathology of disease, as well as validating targets for therapy.—Pat McCaffrey.
Dölen G, Osterweil E, Rao BS, Smith GB, Auerbach BD, Chattarji S, Bear MF. Correction of Fragile X Syndrome in Mice. Neuron. 2007 Dec 20;56(6):955-962. Abstract