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Title: Allosteric activation of M4 muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice.

Authors: Pancani, Tristano; Foster, Daniel J; Moehle, Mark S; Bichell, Terry Jo; Bradley, Emma; Bridges, Thomas M; Klar, Rebecca; Poslusney, Mike; Rook, Jerri M; Daniels, J Scott; Niswender, Colleen M; Jones, Carrie K; Wood, Michael R; Bowman, Aaron B; Lindsley, Craig W; Xiang, Zixiu; Conn, P Jeffrey

Published In Proc Natl Acad Sci U S A, (2015 Nov 10)

Abstract: Mutations that lead to Huntington's disease (HD) result in increased transmission at glutamatergic corticostriatal synapses at early presymptomatic stages that have been postulated to set the stage for pathological changes and symptoms that are observed at later ages. Based on this, pharmacological interventions that reverse excessive corticostriatal transmission may provide a novel approach for reducing early physiological changes and motor symptoms observed in HD. We report that activation of the M4 subtype of muscarinic acetylcholine receptor reduces transmission at corticostriatal synapses and that this effect is dramatically enhanced in presymptomatic YAC128 HD and BACHD relative to wild-type mice. Furthermore, chronic administration of a novel highly selective M4 positive allosteric modulator (PAM) beginning at presymptomatic ages improves motor and synaptic deficits in 5-mo-old YAC128 mice. These data raise the exciting possibility that selective M4 PAMs could provide a therapeutic strategy for the treatment of HD.

PubMed ID: 26508634 Exiting the NIEHS site

MeSH Terms: Allosteric Regulation/physiology*; Animals; Brain/metabolism; Fluorescence; Glutamic Acid/metabolism*; Huntington Disease/drug therapy*; Huntington Disease/physiopathology; Immunohistochemistry; Mice; Mice, Mutant Strains; Pyridazines/pharmacology; Pyridazines/therapeutic use; Receptor, Muscarinic M4/physiology*; Rotarod Performance Test; Synaptic Transmission/drug effects; Synaptic Transmission/physiology*; Thiophenes/pharmacology; Thiophenes/therapeutic use

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