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Allosteric activation of M 4 muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice

Year: 2015
Type: article
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.
DOI: 10.1073/pnas.1512812112
Authors: 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
Language: English
Open Access status: bronze
Funders: Bristol-Myers Squibb, AstraZeneca, Johns Hopkins University, Broad Institute, National Institutes of Health, Stanley Center for Psychiatric Research, Broad Institute, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G3035827077, G3403902456, G4152661918, G540534827, Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Center at Vanderbilt University, G574656479, G5989804218, G63712660, G663594137, G671476491, Udall Parkinson's Disease Center at Emory University: Circuitry to Therapy, Vanderbilt NCDDDG for Discovery of Novel Treatments for Schizophrenia, M1 and M4 mAChRs in striatum-implication in treatment of movement disorders, G8679322781
OpenAlex ID: W2164796994
FWCI: 3.163
Cites: 64
Cited by: 49
Related to: 10