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

Pancani T, Foster DJ, Moehle MS, Bichell TJ, Bradley E, Bridges TM, Klar R, Poslusney M, Rook JM, Daniels JS, Niswender CM, Jones CK, Wood MR, Bowman AB, Lindsley CW, Xiang Z, Conn PJ
Proc Natl Acad Sci U S A. 2015 112 (45): 14078-83

PMID: 26508634 · PMCID: PMC4653197 · DOI:10.1073/pnas.1512812112

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.

MeSH Terms (14)

Allosteric Regulation Animals Brain Fluorescence Glutamic Acid Huntington Disease Immunohistochemistry Mice Mice, Mutant Strains Pyridazines Receptor, Muscarinic M4 Rotarod Performance Test Synaptic Transmission Thiophenes

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