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.
"Pharmacological treatments blocking mGluR-5 receptors can stabilize basal protein translation levels and this approach has been hypothesized as a means of ameliorating some of the core symptoms of FXS, including disorders in intellectual development (Dölen and Bear, 2005; Bhakar et al., 2012). In studies using drosophila KO (dfmr1) and Fmr1 KO murine models, the use of mGluR-5 antagonists has been successful in correcting many features of FXS including elevated and inappropriately expressed protein levels at basal states, decreasing frequency of audiogenic seizures, reversing excessive AMPA internalization, reducing the number of abnormally thin dendritic spines, and reversing behavioral/learning deficits (McBride et al., 2005; Yan et al., 2005; Nakamoto et al., 2007; de Vrij et al., 2008; Pan et al., 2008; Choi et al., 2010; Osterweil et al., 2010; Levenga et al., 2011; Su et al., 2011; Tauber et al., 2011). "
[Show abstract][Hide abstract] 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) signalling, 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 behavioural deficits in 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 behavioural deficit. MPEP treated mice were also less perseverative and impulsive when navigating mazes. Furthermore, MPEP treatment reversed 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 behavioural functioning following pharmacological intervention in FXS.
"This is an important point when considering how to translate these results into mammalian systems. Relevant to this point, studies in the mouse model of fragile X (Fmr1 KO) have shown that genetic reduction or short-term pharmacologic inhibition of group 1 mGluRs or the downstream signaling of group I mGluRs can rescue a wide array of mutant phenotypes (de Vrij et al., 2008; Dolen et al., 2007; Min et al., 2009; Yan et al., 2005). However, it is not known if chronic treatments with lithium or group II mGluR antagonists are effective in the mouse, as they have not been formally tested. "
[Show abstract][Hide abstract] ABSTRACT: Fragile X syndrome is the leading single gene cause of intellectual disabilities. Treatment of a Drosophila model of Fragile X syndrome with metabotropic glutamate receptor (mGluR) antagonists or lithium rescues social and cognitive impairments. A hallmark feature of the Fragile X mouse model is enhanced mGluR-dependent long-term depression (LTD) at Schaffer collateral to CA1 pyramidal synapses of the hippocampus. Here we examine the effects of chronic treatment of Fragile X mice in vivo with lithium or a group II mGluR antagonist on mGluR-LTD at CA1 synapses. We find that long-term lithium treatment initiated during development (5-6 weeks of age) and continued throughout the lifetime of the Fragile X mice until 9-11 months of age restores normal mGluR-LTD. Additionally, chronic short-term treatment beginning in adult Fragile X mice (8 weeks of age) with either lithium or an mGluR antagonist is also able to restore normal mGluR-LTD. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of Fragile X syndrome is an important advance, in that this identifies and validates these targets as potential therapeutic interventions for the treatment of individuals afflicted with Fragile X syndrome.
Brain research 11/2010; 1380:106-19. DOI:10.1016/j.brainres.2010.11.032 · 2.84 Impact Factor
"In conclusion, elucidating the neurobiology associated with reduced FMRP expression with in vivo neuroimaging has the potential for guiding development of disease-specific pharmacological interventions [Bear, 2005; Dolen and Bear, 2005; Yan et al., 2005] and for providing a potential metric for measuring treatment response. Our findings suggest that Cho dysfunction is related to FMRP deficiency in males with FRAX. "
[Show abstract][Hide abstract] ABSTRACT: Males with fragile X syndrome (FRAX) are at risk for significant cognitive and behavioral deficits, particularly those involving executive prefrontal systems. Disruption of the cholinergic system secondary to fragile X mental retardation protein deficiency may contribute to the cognitive-behavioral impairments associated with fragile X. We measured choline in the dorsolateral prefrontal cortex of nine males with FRAX and 9 age-matched typically developing controls using (1)H magnetic resonance spectroscopy. Right choline/creatine was significantly reduced in the fragile X group compared to controls. In controls, both left and right choline was significantly positively correlated with intelligence and age was significantly negatively correlated with left choline. There were no correlations in the fragile X group. Subjects with FRAX participating in a pilot open-label trial of donepezil, an acetylcholinesterase inhibitor, demonstrated significantly improved cognitive-behavioral function. Studies utilizing biochemical neuroimaging techniques such as these have the potential to significantly impact the design of treatment strategies for FRAX and other genetic disorders by helping identify neurochemical targets for intervention as well as serving as metrics for treatment efficacy.
American Journal of Medical Genetics Part A 03/2009; 149A(3):403-7. DOI:10.1002/ajmg.a.32697 · 2.16 Impact Factor
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