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.