Early Alterations in Operant Performance and Prominent Huntingtin Aggregation in a Congenic F344 Rat Line of the Classical CAGn51trunc Model of Huntington Disease.

Anne-Christine Plank,Kerstin A Raber,Olaf Riess,Yvonne K Urbach,Maja Puchades,Hoa H P Nguyen,Julia Dobner,Clarissa Gillmann,Stephan Von Hörsten,Tobias Bäuerle,Jan G Bjaalie,Fabio Canneva

doi:10.3389/fnins.2018.00011

Anne-Christine Plank, Kerstin A Raber + Show 10 more

Open Access

https://doi.org/10.3389/fnins.2018.00011

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Abstract

The transgenic rat model of Huntington disease expressing a fragment of mutant HTT (tgHD rat) has been thoroughly characterized and reproduces hallmark symptoms of human adult-onset HD. Pursuing the optimization of this model for evaluation of translational therapeutic approaches, the F344 inbred rat strain was considered as advantageous genetic background for the expression of the HD transgenic construct. In the present study, a novel congenic line of the SPRDtgHD transgenic model of HD, carrying 51 CAG repeats, was generated on the F344 rat genetic background. To assess the behavioral phenotype, classical assays investigating motor function, emotion, and sensorimotor gating were applied, along with automated screening of metabolic and activity parameters as well as operant conditioning tasks. The neuropathological phenotype was analyzed by immunohistochemistry and ex vivo magnetic resonance imaging. F344tgHD rats displayed markedly reduced anxiety-like behavior in the social interaction test and elevated impulsivity traits already at 3 months of age. Neuropathologically, reduced striatal volume and pronounced aggregation of mutant huntingtin in several brain regions were detected at later disease stage. In conclusion, the congenic F344tgHD model reproduces key aspects of the human HD phenotype, substantiating its value for translational therapeutic approaches.

Highlights

Huntington disease (HD) is an autosomal dominantly inherited, neurodegenerative disorder caused by the expansion of a trinucleotide repeat (>36 CAG) in exon 1 of the huntingtin gene (HTT) on chromosome 4 (The Huntington’s Disease Collaborative Research Group, 1993)
With the objective of optimizing a formerly developed rat model of HD (SPRDtgHD), a new congenic line of the model was created by cross-breeding the transgene in the F344 strain
Our study describes a first characterization of the behavioral and neuropathological phenotype of the newly developed F344tgHD transgenic rat model

Summary

Introduction

Huntington disease (HD) is an autosomal dominantly inherited, neurodegenerative disorder caused by the expansion of a trinucleotide repeat (>36 CAG) in exon 1 of the huntingtin gene (HTT) on chromosome 4 (The Huntington’s Disease Collaborative Research Group, 1993). The resulting aberrant polyglutamine (polyQ) strand elongation in the huntingtin protein induces progressive neuronal atrophy and cell loss in several brain regions, including cerebral cortex, thalamus, hypothalamus and basal ganglia with pronounced degeneration of striatal medium spiny neurons (MSN) (Vonsattel et al, 1985, 2008). Brains of HD patients display significant volume reductions (Rosas et al, 2003), enlargement of the lateral ventricles (LV) as well as neuronal intranuclear inclusions and cytoplasmic aggregates enriched in mutated huntingtin protein (mHTT) (DiFiglia et al, 1997). HD hallmark symptoms comprise motor dysfunction, psychiatric disturbance and cognitive impairment. Movement abnormalities such as chorea and incoordination might be preceded by subtle personality changes and deficits in mental processes, comprising executive functions, attention and memory (Bates et al, 2002). HD is not curable and leads to death after onset of symptoms in midlife within a period of 15–20 years

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