mGlu5 as a potential therapeutic target for the treatment of fragile X syndrome

Fragile X syndrome (FXS) is the most common form of inherited mental retardation and the most common known cause of autism. It is caused by the expansion of a CGG trinucleotide repeat in the 5′ untranslated region of the fragile X mental retardation 1 (FMR1) gene, which encodes the fragile X mental retardation protein (FMRP). FMRP negatively regulates group 1 (Grp 1) metabotropic glutamate receptor (mGlu a.k.a. mGluR) activity, and many FXS phenotypes are thought to be due to the over activity of the Grp 1 mGlu, mGlu5. This review evaluates the evidence for mGlu5 as a potential therapeutic target in the treatment of FXS. A 50% reduction in mGlu5 expression in Fmr1 knockout (KO) mice has been shown to reverse many FXS-relevant phenotypes including alterations in synaptic plasticity, increased dendritic spine density, increased basal hippocampal protein synthesis, inhibitory avoidance extinction and susceptibility to audiogenic seizures. A negative modulator of mGlu5 may, therefore, be expected to have the same effect. In Fmr1 KO mice, Grp 1 mGlu antagonists, such as 2-methyl6-(phenylethynyl)pyridine (MPEP), fenobam and AFQ056, have been shown to reduce audiogenic seizures, reverse altered dendritic spine morphology, reduce excessive protein synthesis and improve behavioural abnormalities. MPEP, however, has failed to reverse altered long-term potentiation in the sensory neocortex or reduce machroorchidism. Clinical trials of mGlu5negative modulators have had some positive outcomes but have had too few participants and were not performed over a long enough period to detect significant effects. Nevertheless, the prospects for development of mGlu5-negative modulators as FXS therapeutics are good and most research supports mGlu5 as a potential therapeutic target.