title: A partial lesion model of Parkinson's disease in mice--characterization of a 6-OHDA-induced medial forebrain bundle lesion.
abstract: The most frequently used animal models for Parkinson's disease (PD) utilize unilateral injection of 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle (MFB), which results in total denervation of the dopaminergic nigrostriatal pathway. However, neuroprotective interventions in PD require models resembling earlier stages of PD, where some dopaminergic cells and fibres remain. The aim of the present study was therefore to establish a MFB partial lesion model in mice. We tested four different 6-OHDA doses, and our results show a dose-dependent loss of nigral dopaminergic cells and striatal fibres that correlated with behavioural impairment in several behavioural tests. Specifically, doses of 0.7 μg and 1 μg of 6-OHDA induced a partial denervation of the nigrostriatal pathway, associated with a mild but quantifiable behavioural impairment. We identified the amphetamine-induced rotation, stepping, corridor and cylinder test to be sensitive enough to select partial lesion animals. Based on our data, we proposed a range of cut-off values for these different behavioural tests to select partial lesion mice. Using a statistical prediction model we identified two behavioural tests (the stepping test and amphetamine-induced rotation test) that with a high sensitivity and specificity predict the extent of nigral dopaminergic cell loss and select mice with a partial nigrostriatal lesion prior to further interventions. This model can serve as an important tool to study neuroprotective therapies for PD in mouse models, especially when the treatment targets the substantia nigra and/or the striatum.
authors.affiliation: Translational Neurology Group, Department of Clinical Sciences, Wallenberg Neuroscience Center, Lund University, Lund, Sweden.
authors.forename: Jordi
authors.initials: J
authors.lastname: Boix
authors.affiliation: Translational Neurology Group, Department of Clinical Sciences, Wallenberg Neuroscience Center, Lund University, Lund, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Padel
authors.affiliation: Translational Neurology Group, Department of Clinical Sciences, Wallenberg Neuroscience Center, Lund University, Lund, Sweden; Department of Neurology, Scania University Hospital, Lund, Sweden. Electronic address: Gesine.paul@med.lu.se.
authors.forename: Gesine
authors.initials: G
authors.lastname: Paul
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D015259:Dopamine Agents / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000473:pathology / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D008474:Medial Forebrain Bundle / Q000473:pathology*; D008562:Membrane Glycoproteins; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000473:pathology* / Q000503:physiopathology*; D012372:ROC Curve; D017472:Receptors, Interleukin-1; D012399:Rotation; D012720:Severity of Illness Index
chemical_list: D015259:Dopamine Agents; D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; D016627:Oxidopamine; D000661:Amphetamine
keywords: 6-Hydroxydopamine; Behavioral test; Medial forebrain bundle; Mouse model; Parkinson's disease; Prediction model