This talk will focus on our work targeting the M1 muscarinic receptor in mouse models of neurodegeneration. Dr. Tobin will build on his published observation that M1-receptor selective positive allosteric modulators can both restore memory deficits and slow disease progression in prion infected mice. Proteomic and transcriptomic studies together with electrophysiological and behavioural experiments provide mechanistic insights with the potential role for diminished neuroinflammation emerging as a hallmark of the M1-protective response.

Rett syndrome (RTT) is a neurodevelopment disorder that is the leading cause of intellectual disability in girls. To identify novel targets for RTT, we performed RNA-sequencing on motor cortex and cerebellum autopsy samples from RTT patients and identified conserved decreases in both subtype 1 (M1) and 4 (M4) muscarinic acetylcholine receptor expression. These findings have now been verified in temporal cortex samples from 45 RTT patient autopsies, and follow up studies demonstrate that M1 and M4 PAMs have efficacy in social, cognitive, and respiratory symptom domains in RTT model mice.

The non-selective muscarinic receptor antagonist trihexyphenidyl is the only oral medication for dystonia that has been proven effective in a double-blind, placebo controlled clinical trial. Unfortunately, most patients cannot use trihexyphenidyl because, at the high doses necessary for efficacy in dystonia, trihexyphenidyl binds to all five mAChR subtypes, resulting in intolerable sides effects. This talk will discuss the use of pharmacologic and genetic approaches in mouse models to identify both specific mAChR subtypes and striatal cell types as novel targets for the treatment of dystonia.