mGluR5 and Preclinical Treatment of Fragile X Syndrome in a Mouse Model

Background: Fragile X is the leading inherited cause of mental retardation and monogenic autism. The disease has been modeled in mice by molecular genetic manipulation of the Fmr1 gene (Fmr1 KO). This gene encodes the Fragile X mental retardation protein (FMRP) and is turned off in human patients with Fragile X. FMRP is an RNA binding protein found in the post-synaptic compartment of neuronal synapses, where is thought to negatively regulate local protein synthesis. The major excitatory neurotransmitter used at central nervous system synapses in mammalian brain is glutamate, and several subtypes of glutamate receptors are found at the post-synapse. Of these the metabotropic glutamate receptor 5 (mGluR5) is unique for its ability to couple activation by glutamate to post-synaptic signaling cascades, including induction of local protein synthesis. Indeed, many of the long-term consequences of mGluR5 activation, including a form of synaptic plasticity called mGluR-LTD, are protein synthesis dependent. Furthermore, mGluR-LTD is exaggerated in Fmr1 KO mice, and is no longer protein synthesis dependent. These findings raise the possibility that the pathogenesis of Fragile X results from dysregulation of mGluR5 mediated protein synthesis, and that this imbalance might be corrected by downregulating mGluR5 mediated signaling.

Objectives: To test the theory that Fragile X results from dysregulation of mGluR5 mediated protein synthesis, and that downregulation of mGluR5 could correct Fragile X phenotypes in Fmr1 KO mice.

Methods: Genetic interaction between Fmr1 and Grm5 (the gene that encodes mGluR5) was tested by generating mice of four genotypes (Wild type, Fmr1 KO, Fmr1 KO/Grm5 Heterozygote, and Grm5 Heterozygote) and comparing phenotypes relevant to the disease (including protein synthesis,mGluR-LTD, in vivo ocular dominance plasticity, behavioral learning and memory, seizure susceptibility, pathologic dendritic spine morphology, abnormal growth trajectory, and macroorchidism) across genotypes.

Results: Seven of eight Fmr1 KO phenotypes tested showed rescue in the Grm5 knockdown background, consistent with genetic interaction between Fmr1 and mGluR5. This interaction implicates mGluR5 as a therapeutic target for the treatment of Fragile X.

Conclusions: These results provide evidence for the use of mGluR5 antagonists in the treatment of Fragile X. Moreover, mGluR5 signaling cascades interact with a number of synaptic proteins, many of which have been implicated in autism, raising the possibility that therapeutic targets identified for Fragile X may have efficacy in treating some, if not all, other causes of autism.