Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2015-11, Vol.112 (45), p.14078-14083

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2015

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.