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Axelrod Symposium: Targeting Muscarinic Acetylcholine Receptors for Treatment of Brain Disorders

Wednesday April 28, 2021

1:30 pm - 3:00 pm Eastern Time (ET)

View session on the EB Virtual Platform (EB registration required)

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Chair :

P. Jeffrey Conn
Vanderbilt Univ. School of Medicine



Muscarinic acetylcholine receptors (mAChRs) play important roles in regulating multiple brain circuits and are potential drug targets for treatment of a range of debilitating brain disorders. However, until recently, highly selective ligands for specific mAChR subtypes have not been available. Recent advances have yielded the first truly selective activators and inhibitors of multiple individual mAChR subtypes. Speakers in this session will outline studies making use of these new tools to provide evidence that subtype-selective mAChR ligands may provide novel approaches for treatment of multiple brain disorders, including schizophrenia, dystonia, Rett syndrome, and neurodegenerative disorders.

Speakers

Andrew Tobin - Univ. of Glasgow

Slowing the Progression of Neurodegenerative Disease – Can Muscarinic Receptors Hold the Answer?

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.

Rocco Gogliotti - Loyola Univ.

Transcriptional Profiling of Autopsy Samples Supports the Development of M1 and M4 PAMs for Rett Syndrome

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.

Ellen Hess - Emory Univ.

Identification of Muscarinic Receptor Subtypes as Targets for the Treatment of Dystonia

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.

Thank you to our Annual Meeting partners:

Amgen
University of Florida
Wake Forest University
Washington State University College of Pharmacy and Pharmaceutical Sciences
University of Wisconsin Molecular and Cellular Pharmacology Training Program
UT Health San Antonio
University of Minnesota

Emory University Pharmacology

PR & P
University of Michigan Medical School Pharmacology
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