Development of a Unilaterally-lesioned 6-OHDA Mouse Model of Parkinson's
Disease |
| |
Authors: | Sherri L Thiele Ruth Warre Joanne E Nash |
| |
Institution: | Centre for Neurobiology of Stress, Dept Biological Sciences, University of Toronto at Scarborough |
| |
Abstract: | The unilaterally lesioned 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson''s
disease (PD) has proved to be invaluable in advancing our understanding of the mechanisms
underlying parkinsonian symptoms, since it recapitulates the changes in basal ganglia
circuitry and pharmacology observed in parkinsonian patients1-4. However, the
precise cellular and molecular changes occurring at cortico-striatal synapses of the
output pathways within the striatum, which is the major input region of the basal ganglia
remain elusive, and this is believed to be site where pathological abnormalities
underlying parkinsonian symptoms arise3,5.In PD, understanding the mechanisms underlying changes in basal ganglia circuitry
following degeneration of the nigro-striatal pathway has been greatly advanced by the
development of bacterial artificial chromosome (BAC) mice over-expressing green
fluorescent proteins driven by promoters specific for the two striatal output pathways
(direct pathway: eGFP-D1; indirect pathway: eGFP-D2 and eGFP-A2a)8, allowing
them to be studied in isolation. For example, recent studies have suggested that there are
pathological changes in synaptic plasticity in parkinsonian mice9,10. However,
these studies utilised juvenile mice and acute models of parkinsonism. It is unclear
whether the changes described in adult rats with stable 6-OHDA lesions also occur in these
models. Other groups have attempted to generate a stable unilaterally-lesioned 6-OHDA
adult mouse model of PD by lesioning the medial forebrain bundle (MFB), unfortunately, the
mortality rate in this study was extremely high, with only 14% surviving the surgery for
21 days or longer11. More recent studies have generated intra-nigral lesions
with both a low mortality rate >80% loss of dopaminergic neurons, however expression of
L-DOPA induced dyskinesia11,12,13,14 was variable in these studies. Another
well established mouse model of PD is the MPTP-lesioned mouse15. Whilst this
model has proven useful in the assessment of potential neuroprotective
agents16, it is less suitable for understanding mechanisms underlying symptoms
of PD, as this model often fails to induce motor deficits, and shows a wide variability
in the extent of lesion17, 18.Here we have developed a stable unilateral 6-OHDA-lesioned mouse model of PD by direct
administration of 6-OHDA into the MFB, which consistently causes >95% loss of striatal
dopamine (as measured by HPLC), as well as producing the behavioural imbalances observed
in the well characterised unilateral 6-OHDA-lesioned rat model of PD. This newly developed
mouse model of PD will prove a valuable tool in understanding the mechanisms underlying
generation of parkinsonian symptoms. |
| |
Keywords: | Medicine Issue 60 mouse 6-OHDA Parkinson’ s disease medial forebrain bundle unilateral |
|
|