Development of a Unilaterally-lesioned 6-OHDA Mouse Model of Parkinson's Disease

The unilaterally lesioned 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson''sdisease (PD) has proved to be invaluable in advancing our understanding of the mechanismsunderlying parkinsonian symptoms, since it recapitulates the changes in basal gangliacircuitry and pharmacology observed in parkinsonian patients^1-4. However, theprecise cellular and molecular changes occurring at cortico-striatal synapses of theoutput pathways within the striatum, which is the major input region of the basal gangliaremain elusive, and this is believed to be site where pathological abnormalitiesunderlying parkinsonian symptoms arise^3,5.In PD, understanding the mechanisms underlying changes in basal ganglia circuitryfollowing degeneration of the nigro-striatal pathway has been greatly advanced by thedevelopment of bacterial artificial chromosome (BAC) mice over-expressing greenfluorescent proteins driven by promoters specific for the two striatal output pathways(direct pathway: eGFP-D1; indirect pathway: eGFP-D2 and eGFP-A2a)⁸, allowingthem to be studied in isolation. For example, recent studies have suggested that there arepathological changes in synaptic plasticity in parkinsonian mice^9,10. However,these studies utilised juvenile mice and acute models of parkinsonism. It is unclearwhether the changes described in adult rats with stable 6-OHDA lesions also occur in thesemodels. Other groups have attempted to generate a stable unilaterally-lesioned 6-OHDAadult mouse model of PD by lesioning the medial forebrain bundle (MFB), unfortunately, themortality rate in this study was extremely high, with only 14% surviving the surgery for21 days or longer¹¹. More recent studies have generated intra-nigral lesionswith both a low mortality rate >80% loss of dopaminergic neurons, however expression ofL-DOPA induced dyskinesia^11,12,13,14 was variable in these studies. Anotherwell established mouse model of PD is the MPTP-lesioned mouse¹⁵. Whilst thismodel has proven useful in the assessment of potential neuroprotectiveagents¹⁶, it is less suitable for understanding mechanisms underlying symptomsof PD, as this model often fails to induce motor deficits, and shows a wide variabilityin the extent of lesion^{17, 18}.Here we have developed a stable unilateral 6-OHDA-lesioned mouse model of PD by directadministration of 6-OHDA into the MFB, which consistently causes >95% loss of striataldopamine (as measured by HPLC), as well as producing the behavioural imbalances observedin the well characterised unilateral 6-OHDA-lesioned rat model of PD. This newly developedmouse model of PD will prove a valuable tool in understanding the mechanisms underlyinggeneration of parkinsonian symptoms.