Profiling metabotropic glutamate receptor 7 expression in Rett syndrome: consequences for pharmacotherapy
Authors
Neuroscience. 2026 01 30; 598().
9-18
Abstract
Rett syndrome (RTT) is caused by mutations in the X-linked methyl-CpG binding protein 2 (MeCP2) transcription factor. RTT patients undergo a developmental regression between 6-18 months of age, resulting in the presentation of symptoms including repetitive behaviors, seizures, autistic-like features, and apneas. We have reported that levels of metabotropic glutamate receptor 7 (mGlu) are significantly decreased in brain samples from RTT patients carrying truncation mutations in the MECP2 gene. Additionally, we have identified decreases in Mecp2 mice and demonstrated that administration of a positive allosteric modulator (PAM) with activity at mGlu 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). We found significant decreases in mGlu, but not mGlu or mGlu, mRNA expression across this larger cohort; additionally, we identified a previously unknown correlation in the expression of mGlu and mGlu in human brain samples. Stratification of RTT patients into those with classically severe versus mild MECP2 pathogenic mutations revealed statistically significant decreases in mGlu expression only in patients with mutations associated with severe symptoms. To establish whether target disruption is required for efficacy, we administered the PAM VU0422288 to mice modeling the mild R306C mutation (Mecp2) and found a significant reduction in apneas. These results provide the first evidence of potentially broad utility for mGlu PAMs in reducing apneas across the RTT spectrum.
Tags: 2026