RT Journal Article
SR Electronic
T1 Motivational, proteostatic and transcriptional deficits precede synapse loss, gliosis and neurodegeneration in the B6.<em>Htt</em><sup><em>Q111/+</em></sup> model of Huntington’s disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 081109
DO 10.1101/081109
A1 Robert M. Bragg
A1 Sydney R. Coffey
A1 Rory M. Weston
A1 Seth A. Ament
A1 Jeffrey P. Cantle
A1 Shawn Minnig
A1 Cory C. Funk
A1 Dominic D. Shuttleworth
A1 Emily L. Woods
A1 Bonnie R. Sullivan
A1 Lindsey Jones
A1 Anne Glickenhaus
A1 John S. Anderson
A1 Michael D. Anderson
A1 Stephen B. Dunnett
A1 Vanessa C. Wheeler
A1 Marcy E. MacDonald
A1 Simon P. Brooks
A1 Nathan D. Price
A1 Jeffrey B. Carroll
YR 2016
UL http://biorxiv.org/content/early/2016/10/14/081109.abstract
AB 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.