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

We have reported that levels of metabotropic glutamate receptor 7 (mGlu₇) are dramatically decreased in brain samples from Rett syndrome patients carrying truncation mutations in theMethyl-CpG Binding Protein 2(MECP2) gene. Additionally, we identified decreases in mGlu₇levels inMecp2^+/-female mice and demonstrated that administration of a positive allosteric modulator (PAM) with activity at mGlu₇corrected 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_4,7and8). We found significant decreases in mGlu₇, but not mGlu₄or mGlu₈, mRNA expression across this larger cohort; additionally, we identified a previously unknown and robust correlation in the expression of mGlu₄and mGlu₈in control individuals. Stratification of RTT patients into individuals with mutations that are clinically correlated with severe versus mild disease revealed statistically significant decreases in mGlu₇expression 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 mGlu₇expression in the brainstem or cortex. These results provide the first evidence of potentially broad utility for mGlu₇PAMs in reducing apneas in RTT patients.