Rodent Models of Huntington's Disease

Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder marked by progressive motor dysfunction, cognitive impairment, and psychiatric disturbances. It results from an expanded CAG repeat within the huntingtin ( htt ) gene, leading to the production of a mutant huntingtin (m-htt) protein that causes widespread neuronal dysfunction and cell death, particularly within the striatum. Although HD was first clinically described in 1872, our mechanistic understanding of the disease has significantly expanded in recent decades, largely owing to the development and utilization of animal models. This chapter offers a comprehensive overview of rodent models of HD, emphasizing their importance in unraveling the pathophysiology of the disease and advancing preclinical therapeutic research. We begin by discussing the molecular underpinnings and clinical manifestations of HD, followed by an in-depth analysis of non-genetic and genetic rodent models. Non-genetic models, generated using neurotoxins, such as quinolinic acid and 3-nitropropionic acid, mimic HD-relevant excitotoxic and metabolic insults. While these models have been instrumental in early pathogenesis studies, the advent of genetic engineering has enabled the development of more disease-specific models. We detail the commonly used transgenic and knock-in mouse and rat models, including R6/1, R6/2, YAC128, BACHD, CAG140, HdhQ150, and zQ175. Each model varies in terms of genetic construct, onset, phenotype severity, and neuropathological features. The advantages and limitations of each model are critically evaluated, with attention to their relevance in replicating human HD pathology and their utility in drug development. By highlighting the strengths and weaknesses of available rodent models, this chapter aims to guide researchers in selecting appropriate models for studying HD mechanisms and evaluating potential therapeutic strategies.