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Dramatic differences in susceptibility to L-DOPA-induced dyskinesia between mice that are aged before or after a nigrostriatal dopamine lesion

Bez, Francesco LU ; Francardo, Veronica LU and Cenci Nilsson, Angela LU (2016) In Neurobiology of Disease 94. p.213-225
Abstract

Mice with striatal 6-hydroxydopamine (6-OHDA) lesions are widely used as a model to study the effects of neurorestorative, symptomatic, or antidyskinetic treatments for Parkinson's disease (PD). The standard praxis is to utilize young adult mice with relatively acute 6-OHDA lesions. However, long post-lesion intervals may be required for longitudinal studies of treatment interventions, and the long-term stability of the model's behavioral and cellular phenotypes is currently unknown. In this study, C57Bl/6J mice sustained unilateral striatal 6-OHDA lesions at approx. 2 months of age, and were allowed to survive for 1, 10 or 22 months. Another group of mice sustained the lesion at the age of 23 months and survived for one month... (More)

Mice with striatal 6-hydroxydopamine (6-OHDA) lesions are widely used as a model to study the effects of neurorestorative, symptomatic, or antidyskinetic treatments for Parkinson's disease (PD). The standard praxis is to utilize young adult mice with relatively acute 6-OHDA lesions. However, long post-lesion intervals may be required for longitudinal studies of treatment interventions, and the long-term stability of the model's behavioral and cellular phenotypes is currently unknown. In this study, C57Bl/6J mice sustained unilateral striatal 6-OHDA lesions at approx. 2 months of age, and were allowed to survive for 1, 10 or 22 months. Another group of mice sustained the lesion at the age of 23 months and survived for one month thereafter. Baseline and drug-induced motor behaviors were examined using a battery of tests (utilizing also a novel video-based methodology). The extent of nigral dopamine cell loss was stable across post-lesion intervals and ages. However, a prominent sprouting of both dopaminergic and serotonergic fibers was detected in the caudate-putamen in animals that survived until 10 and 22 months post-lesion. This phenomenon was associated with a recovery of baseline motor deficits, and with a lack of dyskinetic responses upon treatment with either L-DOPA or apomorphine. By contrast, mice sustaining the lesion at 23 months of age showed a striking susceptibility to the dyskinetic effects of both L-DOPA and apomorphine, which was associated with a pronounced drug-induced upregulation of ∆FosB in the ventrolateral striatum. The results reveal a remarkable compensatory capacity of a damaged nigrostriatal pathway in ageing mice, and how this impacts on the response to dopaminergic therapies for PD.

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publication status
published
subject
keywords
6-Hydroxydopamine, Ageing, Mouse, Neuroplasticity, Parkinson's disease
in
Neurobiology of Disease
volume
94
pages
13 pages
publisher
Elsevier
external identifiers
  • scopus:84977266542
  • wos:000381836700020
ISSN
0969-9961
DOI
10.1016/j.nbd.2016.06.005
language
English
LU publication?
yes
id
ab03b559-be39-4f9d-840c-29508e367328
date added to LUP
2016-07-26 07:33:08
date last changed
2017-08-13 04:56:55
@article{ab03b559-be39-4f9d-840c-29508e367328,
  abstract     = {<p>Mice with striatal 6-hydroxydopamine (6-OHDA) lesions are widely used as a model to study the effects of neurorestorative, symptomatic, or antidyskinetic treatments for Parkinson's disease (PD). The standard praxis is to utilize young adult mice with relatively acute 6-OHDA lesions. However, long post-lesion intervals may be required for longitudinal studies of treatment interventions, and the long-term stability of the model's behavioral and cellular phenotypes is currently unknown. In this study, C57Bl/6J mice sustained unilateral striatal 6-OHDA lesions at approx. 2 months of age, and were allowed to survive for 1, 10 or 22 months. Another group of mice sustained the lesion at the age of 23 months and survived for one month thereafter. Baseline and drug-induced motor behaviors were examined using a battery of tests (utilizing also a novel video-based methodology). The extent of nigral dopamine cell loss was stable across post-lesion intervals and ages. However, a prominent sprouting of both dopaminergic and serotonergic fibers was detected in the caudate-putamen in animals that survived until 10 and 22 months post-lesion. This phenomenon was associated with a recovery of baseline motor deficits, and with a lack of dyskinetic responses upon treatment with either L-DOPA or apomorphine. By contrast, mice sustaining the lesion at 23 months of age showed a striking susceptibility to the dyskinetic effects of both L-DOPA and apomorphine, which was associated with a pronounced drug-induced upregulation of ∆FosB in the ventrolateral striatum. The results reveal a remarkable compensatory capacity of a damaged nigrostriatal pathway in ageing mice, and how this impacts on the response to dopaminergic therapies for PD.</p>},
  author       = {Bez, Francesco and Francardo, Veronica and Cenci Nilsson, Angela},
  issn         = {0969-9961},
  keyword      = {6-Hydroxydopamine,Ageing,Mouse,Neuroplasticity,Parkinson's disease},
  language     = {eng},
  month        = {10},
  pages        = {213--225},
  publisher    = {Elsevier},
  series       = {Neurobiology of Disease},
  title        = {Dramatic differences in susceptibility to L-DOPA-induced dyskinesia between mice that are aged before or after a nigrostriatal dopamine lesion},
  url          = {http://dx.doi.org/10.1016/j.nbd.2016.06.005},
  volume       = {94},
  year         = {2016},
}