Phenotypical variability in the 6-OHDA mouse model of Parkinson's disease despite consistent and robust nigral lesioning

Animal models of Parkinson’s disease (PD) based on neurodegenerative neurotoxins are essential preclinical tools for studying the disorder. In mice, intracranial infusion of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB) induces a severe lesion of the nigrostriatal pathway, mimicking the advanced stage of PD, when dopaminergic (DA) cell loss in the substantia nigra pars compacta (SNc) exceeds 95%. In contrast, intrastriatal infusion of 6-OHDA produces a milder lesion, modeling earlier disease stages. This latter model is mainly used to investigate possible compensatory mechanisms that delay the onset of motor deficits before DA depletion becomes extensive. Here, we present results from a study using the MFB 6-OHDA mouse model, in which a subset of animals with over 95% DA cell loss in the SNc exhibited neither acute nor chronic toxin-induced symptoms. To exclude the possibility that the absence of a PD phenotype resulted from inconsistent dopaminergic lesioning, we conducted a detailed analysis of dopaminergic cells and fibers in both the nigrostriatal and mesolimbic systems. Comparable lesions were observed in both typical and atypical PD mice. This finding suggests the presence of compensatory mechanisms in the MFB model that thus far may have been overlooked, given that this model is generally assumed to produce stable and severe motor deficits. Notably, animals that fail to display a robust parkinsonian phenotype are often excluded early in experiments under the assumption of an incomplete SNc lesion, which may introduce significant bias in preclinical PD research. • A subset of mice with >95% dopaminergic cell loss in the SNc displayed no PD phenotype. • Typical and atypical PD mice exhibited comparable nigrostriatal and mesolimbic lesions. • Possible compensatory mechanisms may underlie the absence of PD symptoms in atypical mice. • Lack of behavioral symptoms does not necessarily indicate an unsuccessful lesion in PD mouse models.