HttQ111/+ Huntington's Disease Knock-in Mice Exhibit Brain Region-Specific Morphological Changes and Synaptic Dysfunction

Journal of Huntington's Disease
Marina KovalenkoVanessa C Wheeler

Abstract

Successful disease-modifying therapy for Huntington's disease (HD) will require therapeutic intervention early in the pathogenic process. Achieving this goal requires identifying phenotypes that are proximal to the HTT CAG repeat expansion. To use Htt CAG knock-in mice, precise genetic replicas of the HTT mutation in patients, as models to study proximal disease events. Using cohorts of B6J.HttQ111/+ mice from 2 to 18 months of age, we analyzed pathological markers, including immunohistochemistry, brain regional volumes and cortical thickness, CAG instability, electron microscopy of striatal synapses, and acute slice electrophysiology to record glutamatergic transmission at striatal synapses. We also incorporated a diet perturbation paradigm for some of these analyses. B6J.HttQ111/+ mice did not exhibit significant neurodegeneration or gliosis but revealed decreased striatal DARPP-32 as well as subtle but regional-specific changes in brain volumes and cortical thickness that parallel those in HD patients. Ultrastructural analyses of the striatum showed reduced synapse density, increased postsynaptic density thickness and increased synaptic cleft width. Acute slice electrophysiology showed alterations in spontaneous AMPA recepto...Continue Reading

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Citations

Aug 15, 2020·Science·Marian DiFiglia
Jun 5, 2020·Acta Neuropathologica Communications·Ting-Ting HuangJia-Yi Li
May 17, 2019·Journal of Neurochemistry·Amy I Smith-DijakLynn A Raymond
Apr 15, 2020·International Journal of Molecular Sciences·Francesca OppedisanoVincenzo Mollace
Jan 12, 2021·Frontiers in Cell and Developmental Biology·Magdalena Czeredys
Feb 14, 2021·Journal of Huntington's Disease·Ravi R Iyer, Anna Pluciennik
Apr 6, 2021·Frontiers in Synaptic Neuroscience·Maria IulianoKimberly B Kegel-Gleason

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Methods Mentioned

BETA
electron microscopy
genotyping
PCR
Profiler
dissection

Software Mentioned

Stereo Investigator
ImageJ
Cell Profiler
GeneMapper

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