Neuron
Volume 74, Issue 1, 12 April 2012, Pages 49-56
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Chronic Pharmacological mGlu5 Inhibition Corrects Fragile X in Adult Mice

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Summary

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. Previous studies have implicated mGlu5 in the pathogenesis of the disease, but a crucial unanswered question is whether pharmacological mGlu5 inhibition is able to reverse an already established FXS phenotype in mammals. Here we have used the novel, potent, and selective mGlu5 inhibitor CTEP to address this issue in the Fmr1 knockout mouse. Acute CTEP treatment corrects elevated hippocampal long-term depression, protein synthesis, and audiogenic seizures. Chronic treatment that inhibits mGlu5 within a receptor occupancy range of 81% ± 4% rescues cognitive deficits, auditory hypersensitivity, aberrant dendritic spine density, overactive ERK and mTOR signaling, and partially corrects macroorchidism. This study shows that a comprehensive phenotype correction in FXS is possible with pharmacological intervention starting in young adulthood, after development of the phenotype. It is of great interest how these findings may translate into ongoing clinical research testing mGlu5 inhibitors in FXS patients.

Highlights

► A new compound, CTEP, was used to achieve chronic in vivo inhibition of mGlu5 ► Uninterrupted partial mGlu5 blockade corrected multiple phenotypes in Fmr1 KO mice ► Proof of principle that FXS can be ameliorated by targeting mGlu5 in adult mammals ► Many FXS deficits might be caused by altered signaling versus derailed development

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These authors contributed equally to this work