Clinical and Preclinical Evidence for M(1) Muscarinic Acetylcholine Receptor Potentiation as a Therapeutic Approach for Rett Syndrome

Rett syndrome (RTT) is a neurodevelopmental disorder that is characterized by developmental regression, loss of communicative ability, stereotyped hand wringing, cognitive impairment, and central apneas, among many other symptoms. RTT is caused by loss-of-function mutations in a methyl-reader known as methyl-CpG-binding protein 2 (MeCP2), a protein that links epigenetic changes on DNA to larger chromatin structure. Historically, target identification for RTT has relied heavily on Mecp2 knockout mice; however, we recently adopted the alternative approach of performing transcriptional profiling in autopsy samples from RTT patients. Through this mechanism, we identified muscarinic acetylcholine receptors (mAChRs) as potential therapeutic targets. Here, we characterized a cohort of 40 temporal cortex samples from individuals with RTT and quantified significantly decreased levels of the M(1), M(2), M(3), and M(5) mAChRs subtypes relative to neurotypical controls. Of these four subtypes, M(1) expression demonstrated a linear relationship with MeCP2 expression, such that M(1) levels were only diminished in contexts where MeCP2 was also significantly decreased. Further, we show that M(1) potentiation with the positive allosteric modulator (PAM) VU0453595 (VU595) rescued social preference, spatial memory, and associative memory deficits, as well as decreased apneas in Mecp2(+/-) mice. VU595’s efficacy on apneas in Mecp2(+/-) mice was mediated by the facilitation of the transition from inspiration to expiration. Molecular analysis correlated rescue with normalized global gene expression patterns in the brainstem and hippocampus, as well as increased Gsk3β inhibition and NMDA receptor trafficking. Together, these data suggest that M(1) PAMs could represent a new class of RTT therapeutics. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-022-01254-3.