Motivational, proteostatic and transcriptional deficits precede synapse loss, gliosis and neurodegeneration in the B6.HttQ111/+model of Huntington's disease.
We investigated the appearance and progression of disease-relevant signs in the B6.HttQ111/+mouse, a genetically precise model of the mutation that causes Huntington's disease (HD). We find that B6.HttQ111/+mice are healthy, show no overt signs of central or peripheral inflammation, and no gross motor impairment as late as 12 months of age. Behaviorally, we find that 4-9 month old B6.HttQ111/+mice have normal activity levels and show no clear signs of anxiety or depression, but do show clear signs of reduced motivation. The neuronal density, neuronal size, synaptic density and number of glia is normal in B6.HttQ111/+striatum, the most vulnerable brain region in HD, up to 12 months of age. Despite this preservation of the synaptic and cellular composition of the striatum, we observe clear progressive, striatal-specific transcriptional dysregulation and accumulation of neuronal intranuclear inclusions (NIIs). Simulation studies suggest these molecular endpoints are sufficiently robust for future preclinical studies, and that B6.HttQ111/+mice are a useful tool for modeling disease-modifying or neuroprotective strategies for disease processes before the onset of overt phenotypes.
Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, WA, USA.
Robert M
RM
Bragg
Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, WA, USA.
Sydney R
SR
Coffey
Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, WA, USA.|Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
Rory M
RM
Weston
Institute for Systems Biology, Seattle, WA, USA.|Institute for Genome Sciences and Department of Psychiatry, University of Maryland School of Medicine, Baltimore, USA.
Seth A
SA
Ament
Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, WA, USA.
Jeffrey P
JP
Cantle
Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, WA, USA.
Shawn
S
Minnig
Institute for Systems Biology, Seattle, WA, USA.
Cory C
CC
Funk
Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, WA, USA.
Dominic D
DD
Shuttleworth
Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, WA, USA.
Emily L
EL
Woods
Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, WA, USA.
Bonnie R
BR
Sullivan
Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, WA, USA.
Lindsey
L
Jones
Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, WA, USA.
Anne
A
Glickenhaus
Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, WA, USA.
John S
JS
Anderson
Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, WA, USA.
Michael D
MD
Anderson
The Brain Repair Group, Cardiff University School of Biosciences, The Sir Martin Evans Building, Museum Avenue, Cardiff, Wales CF10 3AX, United Kingdom.
Stephen B
SB
Dunnett
Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston 02114, MA, USA.
Vanessa C
VC
Wheeler
Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston 02114, MA, USA.
Marcy E
ME
MacDonald
The Brain Repair Group, Cardiff University School of Biosciences, The Sir Martin Evans Building, Museum Avenue, Cardiff, Wales CF10 3AX, United Kingdom.
Simon P
SP
Brooks
Institute for Systems Biology, Seattle, WA, USA.
Nathan D
ND
Price
Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, WA, USA.|Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston 02114, MA, USA.
Jeffrey B
JB
Carroll