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.
Highlights
Fragile X Syndrome (FXS) is a neurodevelopmental disorder that is caused by the loss of function mutation of the fragile X mental retardation 1 (Fmr1) gene on the X chromosome resulting in lack of fragile X mental retardation protein (FMRP) expression (Fu et al, 1991; Pieretti et al, 1991)
Much research on, long-term depression (LTD) in fragile X mental retardation 1 knock-out (Fmr1 KO) mice, the prevailing opinion is that Fmrp, which binds to approximately 4% of total brain mRNA (Brown et al, 2001; Darnell et al, 2011), acts as a translational suppressor of proteins in vivo, many of which are implicated in synaptic plasticity (Bassell and Warren, 2008; Darnell et al, 2011; Bhakar et al, 2012)
FXS is a debilitating mental, physical, and behavioral condition that occurs due to lack of expression of the Fragile X Mental Retardation 1 protein (FMRP; reviewed in Santoro et al, 2012)
Summary
Fragile X Syndrome (FXS) is a neurodevelopmental disorder that is caused by the loss of function mutation of the fragile X mental retardation 1 (Fmr1) gene on the X chromosome (reviewed in O’Donnell and Warren, 2002; Santoro et al, 2012; Online Mendelian Inheritance in Man ® [OMIM] 309550) resulting in lack of fragile X mental retardation protein (FMRP) expression (Fu et al, 1991; Pieretti et al, 1991). Lack of FMRP results in a number of symptoms including disorders of intellectual development, attention deficit and hyperactivity, anxiety, epilepsy, as well as particular physical features such as an elongated face and macroorchidism (Hagerman, 1996; Turner et al, 1996; O’Donnell and Warren, 2002; Hatton et al, 2006; Sullivan et al, 2006; Scerif et al, 2007). Much research on, LTD in Fmr KO mice, the prevailing opinion is that Fmrp, which binds to approximately 4% of total brain mRNA (Brown et al, 2001; Darnell et al, 2011), acts as a translational suppressor of proteins in vivo, many of which are implicated in synaptic plasticity (Bassell and Warren, 2008; Darnell et al, 2011; Bhakar et al, 2012)
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