Profiling metabotropic glutamate receptor 7 expression in Rett syndrome: consequences for pharmacotherapy

We have reported that levels of metabotropic glutamate receptor 7 (mGlu ₇ ) are dramatically decreased in brain samples from Rett syndrome patients carrying truncation mutations in the Methyl-CpG Binding Protein 2 ( MECP2 ) gene. Additionally, we identified decreases in mGlu ₇ levels in Mecp2 ^+/- female mice and demonstrated that administration of a positive allosteric modulator (PAM) with activity at mGlu ₇ corrected deficits in cognitive, social, and respiratory domains. Here, we expanded our studies to a larger cohort of RTT samples covering a range of mutations and evaluated expression of the three widely expressed group III mGlu receptors (mGlu _{4,7 and 8} ). We found significant decreases in mGlu ₇ , but not mGlu ₄ or mGlu ₈ , mRNA expression across this larger cohort; additionally, we identified a previously unknown and robust correlation in the expression of mGlu ₄ and mGlu ₈ in control individuals. Stratification of RTT patients into individuals with mutations that are clinically correlated with severe versus mild disease revealed statistically significant decreases in mGlu ₇ expression only in patients with mutations that induce more severe symptoms. We then administered the PAM VU0422288 to mice modeling the mild R306C mutation ( Mecp2 ^R306C/+ ) and found a significant reduction in apneas induced by VU0422888 administration despite no decreases in mGlu ₇ expression in the brainstem or cortex. These results provide the first evidence of potentially broad utility for mGlu ₇ PAMs in reducing apneas in RTT patients.