Fragile X syndrome (FXS) results from transcriptional silencing of FMR1; however, it is unclear how this silencing leads to the pathological features of the syndrome. In a new study, Bear and colleagues sought evidence to support their theory that the neurological aspects of the syndrome might result from excessive signalling through group-1 metabotropic glutamate receptors (mGluRs).
Previously, the authors had suggested that fragile X mental retardation protein (FMRP) opposes the actions of group 1 mGluRs at the synapse, and that loss of this regulation leads to FXS; however, they had only indirect evidence to back up their hypothesis. Here they tested the theory directly by crossing two transgenic mouse lines: one in which Fmr1 was knocked out (Fmr1-KO mice) and one in which levels of mGluR5 were reduced by 50%. Fmr1-KO mice display many neurological dysfunctions that are similar to FXS symptoms. The authors investigated whether the reduction in mGluR5 levels in the double mutants would correct some of these deficits.
Both neural development and cognitive functions, such as memory, are dysfunctional in FXS. The reduction in mGluR5 in the double mutants returned ocular dominance plasticity and the density of dendritic spines on cortical pyramidal neurons (both of which are enhanced in Fmr1-KO mice) to control levels. One downstream action of mGluRs that can be regulated by FMRP is their ability to promote synaptic protein synthesis. Indeed, an increase in total protein synthesis was observed in the hippocampus of Fmr1-KO mice and was reversed in the double mutants.
To examine the effects of the mutations on cognitive function, the authors used a behavioural paradigm that examined the acquisition and subsequent extinction of a learned association between a dark chamber and an unpleasant stimulus. Fmr1-KO mice exhibited higher levels of extinction than control mice, which might relate to the cognitive impairments that are seen in FXS individuals. This was reversed in the mice that carried both mutations. In another clinically relevant test, the authors showed that the double-mutant mice had reduced susceptibility to seizures.
This study provides evidence that supports the idea that some features of FXS might be caused by runaway mGluR activity, and that reducing this activity might correct these defects. It hence paves the way for new therapeutic approaches.