Article

Courting a cure for fragile X.

Howard Hughes Medical Institute, The Picower Center for Learning and Memory, Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Neuron (Impact Factor: 15.98). 04/2005; 45(5):642-4. DOI: 10.1016/j.neuron.2005.02.021
Source: PubMed

ABSTRACT Fragile X syndrome is the most common heritable cause of mental retardation. Previous work has suggested that overactive signaling by group I metabotropic glutamate receptors (mGluRs) may be a mechanism underlying many of the disease symptoms. As a test of this theory, McBride et al. show that in a Drosophila model for Fragile X syndrome, treatment with mGluR antagonists can rescue short-term memory, courtship, and mushroom body defects.

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    ABSTRACT: Fragile X Syndrome (FXS) is caused by the lack of expression of the fragile X mental retardation protein (FMRP), which results in intellectual disability and other debilitating symptoms including impairment of visual-spatial functioning. FXS is the only single-gene disorder that is highly co-morbid with autism spectrum disorder and can therefore provide insight into its pathophysiology. Lack of FMRP results in altered group I metabotropic glutamate receptor (mGluR) signaling, which is a target for putative treatments. The Hebb-Williams (H-W) mazes are a set of increasingly complex spatial navigation problems that depend on intact hippocampal and thus mGluR-5 functioning. In the present investigation, we examined whether an antagonist of mGluR-5 would reverse previously described behavioral deficits in fragile X mental retardation 1 knock-out (Fmr1 KO) mice. Mice were trained on a subset of the H-W mazes and then treated with either 20 mg/kg of an mGluR-5 antagonist, 2-Methyl-6-(phenylethynyl) pyridine (MPEP; n = 11) or an equivalent dose of saline (n = 11) prior to running test mazes. Latency and errors were dependent variables recorded during the test phase. Immediately after completing each test, marble-burying behavior was assessed, which confirmed that the drug treatment was pharmacologically active during maze learning. Although latency was not statistically different between the groups, MPEP treated Fmr1 KO mice made significantly fewer errors on mazes deemed more difficult suggesting a reversal of the behavioral deficit. MPEP treated mice were also less perseverative and impulsive when navigating mazes. Furthermore, MPEP treatment reversed post-synaptic density-95 (PSD-95) protein deficits in Fmr1 KO treated mice, whereas levels of a control protein (β-tubulin) remained unchanged. These data further validate MPEP as a potentially beneficial treatment for FXS. Our findings also suggest that adapted H-W mazes may be a useful tool to document alterations in behavioral functioning following pharmacological intervention in FXS.
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    ABSTRACT: Introduction: Fragile X syndrome (FXS), the most common inherited form of intellectual disability and autism, is caused by expansion of CGG trinucleotide repeats in FMR1 and marked reduction or absence of the gene product, FMRP. FMRP suppresses synaptic protein synthesis resulting from group 1 metabotropic glutamate receptor (mGluR) activation, a process critical to normal synaptic plasticity. FXS can be characterized as a disorder of synaptic plasticity with physical, cognitive and behavioral manifestations attributable to, at least in part, excessive mGluR activity and downstream effects. Areas covered: This paper reviews the ‘mGluR theory' of FXS and the targeted drugs investigated in Phase II and III trials based on this theory of pathogenesis. A literature review was conducted using the PubMed database with search terms ‘fragile X syndrome', ‘mGluRs', ‘pharmacotherapy' and specific drug-related terms. Other resources were identified by review of relevant reference lists and consultation with experts in the field. Expert opinion: While preclinical trials of targeted drugs in animal models of FXS have been encouraging, more studies are needed to determine clinical efficacy in humans. Challenges to clinical trial design and direction for future drug studies, including consideration of NMDA receptor partial agonists and mGluR2/3 agonists, are discussed.
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