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

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

*Corresponding author for this work

Research output: Contribution to journalArticle

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)14078-14083
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number45
DOIs
StatePublished - Nov 10 2015

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Allosteric activation of M4 muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice'. Together they form a unique fingerprint.

  • Cite this

    Pancani, T., Foster, D. J., Moehle, M. S., Bichell, T. J., Bradley, E., Bridges, T. M., Klar, R., Poslusney, M., Rook, J. M., Scott Daniels, J., Niswender, C. M., Jones, C. K., Wood, M. R., Bowman, A. B., Lindsley, C. W., Xiang, Z., & Jeffrey Conn, P. (2015). Allosteric activation of M4 muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice. Proceedings of the National Academy of Sciences of the United States of America, 112(45), 14078-14083. https://doi.org/10.1073/pnas.1512812112