Optimized Administration of the M₄ PAM VU0467154 Demonstrates Broad Efficacy, but Limited Effective Concentrations in Mecp2^+/- Mice.

ABSTRACT: Hypofunction of cholinergic circuits and diminished cholinergic tone have been associated with the neurodevelopmental disorder Rett syndrome (RTT). Specifically, deletion of Mecp2 in cholinergic neurons evokes the same social and cognitive phenotypes in mice seen with global Mecp2 knockout, and decreased choline acetyltransferase activity and vesamicol binding have been reported in RTT autopsy samples. Further, we recently identified significant decreases in muscarinic acetylcholine receptor subtype 4 (M₄) expression in both the motor cortex and cerebellum of RTT patient autopsies and established proof of concept that an acute dose of the positive allosteric modulator (PAM) VU0467154 (VU154) rescued phenotypes in Mecp2^+/- mice. Here, we exp

SUBMITTER: Cikowski J 

PROVIDER: S-EPMC9266622 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature