Abstract
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.