- The quinolinic acid (QA)-lesioned rodent model is a well-established experimental system used to study the neuropathological and behavioral consequences of Huntington’s disease (HD).
- Quinolinic acid is an endogenous neurotoxin and a metabolite of the kynurenine pathway of tryptophan degradation. It acts as an agonist at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, producing excitotoxic neuronal death through sustained calcium influx, generation of reactive oxygen species, mitochondrial dysfunction, and activation of apoptotic cascades.
- In the context of HD research, QA is stereotaxically injected into the striatum—the brain region most affected in HD—of rodents, resulting in selective degeneration of medium spiny neurons (MSNs) that closely resembles the pattern of neuronal loss seen in human patients.
- The model was first introduced in the early 1980s when researchers discovered that direct intrastriatal administration of QA could mimic the striatal atrophy, gliosis, and neurochemical imbalances observed in HD. Unlike mechanical lesions or non-selective chemical toxins, QA preferentially damages neurons while largely sparing glial cells and interneurons, thereby reproducing the neuroanatomical specificity of HD pathology. Additionally, the lesion is unilateral in many studies, which allows the contralateral hemisphere to serve as an internal control for histological and behavioral comparisons. The extent of neuronal loss can be modulated by varying the dose, injection site, and volume of QA, enabling researchers to model different severities of the disease.
- Behaviorally, QA-lesioned rodents display a range of motor deficits akin to those in HD patients, including hyperkinesia, dystonia, and impaired motor coordination. These can be quantified using tasks such as the rotarod, open field activity monitoring, and grip strength testing. In addition to motor impairments, some animals develop cognitive and emotional disturbances, reflecting the involvement of corticostriatal circuits in non-motor aspects of HD. Importantly, the unilateral lesion design often produces rotational asymmetry in locomotor behavior when animals are challenged with dopaminergic agents, a feature that facilitates pharmacological assessments.
- From a neurochemical standpoint, QA lesions cause a marked reduction in striatal GABA and substance P levels, with concomitant changes in dopamine receptor binding and glutamate receptor subunit expression. This mirrors many of the neurochemical alterations observed in HD patients. The excitotoxic nature of QA also triggers inflammatory responses, including microglial activation and astrocytosis, providing a platform for studying neuroinflammation’s role in HD progression. These cellular and molecular parallels make the QA model valuable for testing neuroprotective strategies targeting excitotoxicity, oxidative stress, mitochondrial function, and inflammatory pathways.
- However, while the QA-lesioned rodent model reproduces several key features of HD, it is an acute, non-genetic model and does not capture the progressive, genetically driven nature of the human disease. It lacks the full spectrum of systemic symptoms and molecular changes caused by mutant huntingtin protein, such as protein aggregation and transcriptional dysregulation. Therefore, QA lesions are often used in conjunction with transgenic HD models to cross-validate findings and to focus specifically on excitotoxic mechanisms. Despite these limitations, the QA model remains one of the most widely used and reliable systems for rapid, reproducible screening of potential therapeutic compounds that aim to protect striatal neurons from excitotoxic death.
