Allosteric activation of M4 muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice.
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.
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232;
Tristano
T
Pancani
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232;
Daniel J
DJ
Foster
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232;
Mark S
MS
Moehle
Department of Neurology, Vanderbilt University, Nashville, TN 37232;
Terry Jo
TJ
Bichell
Department of Neurology, Vanderbilt University, Nashville, TN 37232;
Emma
E
Bradley
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232;
Thomas M
TM
Bridges
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232;
Rebecca
R
Klar
Lieber Institute for Brain Development, Baltimore, MD 21205.
Mike
M
Poslusney
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232;
Jerri M
JM
Rook
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232;
J Scott
JS
Daniels
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232;
Colleen M
CM
Niswender
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232;
Carrie K
CK
Jones
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232;
Michael R
MR
Wood
Department of Neurology, Vanderbilt University, Nashville, TN 37232;
Aaron B
AB
Bowman
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232;
Craig W
CW
Lindsley
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232; zixiu.xiang@vanderbilt.edu jeff.conn@vanderbilt.edu.
Zixiu
Z
Xiang
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232; zixiu.xiang@vanderbilt.edu jeff.conn@vanderbilt.edu.
P Jeffrey
PJ
Conn
D000494:Allosteric Regulation / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D005453:Fluorescence; D018698:Glutamic Acid / Q000378:metabolism*; D006816:Huntington Disease / Q000188:drug therapy* / Q000503:physiopathology; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D011724:Pyridazines / Q000494:pharmacology / Q000627:therapeutic use; D043588:Receptor, Muscarinic M4 / Q000502:physiology*; D045442:Rotarod Performance Test; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use
C000599366:5-amino-3,4-dimethyl-N-(4-((trifluoromethyl)sulfonyl)benzyl)thieno(2,3-c)pyridazine-6-carboxamide; D011724:Pyridazines; D043588:Receptor, Muscarinic M4; D013876:Thiophenes; D018698:Glutamic Acid
basal ganglia; movement disorder; neurodegenerative; trinucleotide repeat disorder