Striatal signaling in the treatment of Parkinson's disease
(2016)- Abstract
- Parkinson’s disease (PD) is a neurodegenerative disorder characterized by typical motor symptoms that are caused by depletion of dopamine (DA) in the striatum. These symptoms are treated with the DA precursor L-DOPA, or with DA receptor (DAR) agonists. L-DOPA is the most efficacious treatment, but causes complications that limit its utility, in particular, dyskinesia (involuntary movements). Models of L-DOPA-induced dyskinesia can be obtained in rats and mice sustaining nigrostriatal DA lesions and treatment with L-DOPA. In these animal models, the induction of abnormal involuntary movements (AIMs) by L-DOPA is correlated with a large activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in striatal spiny projection neurons... (More)
- Parkinson’s disease (PD) is a neurodegenerative disorder characterized by typical motor symptoms that are caused by depletion of dopamine (DA) in the striatum. These symptoms are treated with the DA precursor L-DOPA, or with DA receptor (DAR) agonists. L-DOPA is the most efficacious treatment, but causes complications that limit its utility, in particular, dyskinesia (involuntary movements). Models of L-DOPA-induced dyskinesia can be obtained in rats and mice sustaining nigrostriatal DA lesions and treatment with L-DOPA. In these animal models, the induction of abnormal involuntary movements (AIMs) by L-DOPA is correlated with a large activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in striatal spiny projection neurons (SPNs).
Work in the present thesis has aimed at (i) identifying molecular pathways involved in the large induction of ERK1/2 by L-DOPA (Papers I and III); (ii) optimizing rating scales to assess L-DOPA-induced dyskinesia (LID) in the mouse, to compare the efficacy of several subtype-specific DAR antagonists (Paper II); (iii) applying cell type-specific chemogenetics to determine how the two main types of SPNs contribute to therapeutic vs. dyskinetic effects of L-DOPA (Paper IV). Our results reveal that L-DOPA-induced ERK1/2 depends on an interaction between D1R and calcium-dependent pathways, which are critically modulated by metabotropic glutamate receptor type 5 (mGluR5). Antagonizing mGluR5 or its downstream effectors, such as phospholipase C (PLC), inhibits striatal ERK1/2 activation both ex vivo and in vivo. Moreover, in vivo antagonism of mGluR5 and PLC reduces D1R-dependent AIMs in rat and mouse models of dyskinesia. The same treatments do not affect dyskinesia provoked by the stimulation of D2 receptors (D2R), which is supposed to depend on striatal neurons of the indirect pathway (D2R-expressing). To dissect the contribution of D1R- and D2R-expressing neurons to dyskinesia, we used viral vector-mediated chemogenetics. The results show that both cell types contribute to LID with opposite modulatory roles. Stimulation of D1R-expressing SPNs amplifies both L-DOPA therapeutic and dyskinetic action, while activation of D2R-expressing SPNs inhibits them. Induction of AIMs is promoted by the recruitment of signaling mechanisms that mimic D1R activation. However, maximally severe AIMs are reproduced by concomitant activation of both D1R- and D2R-expressing SPNs, thus underlying the concurrent role of both pathways in the development of LID. Through the use of a novel scale for rating AIMs in the mouse model of PD, we also unraveled the anti-dyskinetic potential of several DAR antagonists. We found that antagonism of D1R, D2R, D3R and D4R reduced L-DOPA-induced AIMs with a treatment-specific anti-dyskinetic profile, thus pointing to an involvement of all DARs in the modulation of LID. Taken together, the results included in this thesis provide new insights on the signaling pathways and neural circuits through which the dopaminergic treatment of PD affects motor behaviors. Moreover, the work in this thesis contributes to methodological advances to preclinical research on PD and LID.
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Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/06553799-e007-47b0-83aa-72097cac9046
- author
- Sebastianutto, Irene LU
- supervisor
- opponent
-
- professor Jung Kang, Un, New York, USA
- organization
- publishing date
- 2016
- type
- Thesis
- publication status
- published
- subject
- pages
- 99 pages
- publisher
- Lund University: Faculty of Medicine
- defense location
- Segerfalksalen, Wallenberg Neurocentrum, BMC, Sölvegatan 17, Lund.
- defense date
- 2016-12-16 13:15:00
- ISBN
- 978-91-7619-379-2
- language
- English
- LU publication?
- yes
- additional info
- ISSN: 1652-8220 Lund University, Faculty of Medicine Doctoral Dissertation Series 2016:151
- id
- 06553799-e007-47b0-83aa-72097cac9046
- date added to LUP
- 2016-11-23 21:48:36
- date last changed
- 2019-11-19 13:49:58
@phdthesis{06553799-e007-47b0-83aa-72097cac9046,
abstract = {{Parkinson’s disease (PD) is a neurodegenerative disorder characterized by typical motor symptoms that are caused by depletion of dopamine (DA) in the striatum. These symptoms are treated with the DA precursor L-DOPA, or with DA receptor (DAR) agonists. L-DOPA is the most efficacious treatment, but causes complications that limit its utility, in particular, dyskinesia (involuntary movements). Models of L-DOPA-induced dyskinesia can be obtained in rats and mice sustaining nigrostriatal DA lesions and treatment with L-DOPA. In these animal models, the induction of abnormal involuntary movements (AIMs) by L-DOPA is correlated with a large activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in striatal spiny projection neurons (SPNs).<br/>Work in the present thesis has aimed at (i) identifying molecular pathways involved in the large induction of ERK1/2 by L-DOPA (Papers I and III); (ii) optimizing rating scales to assess L-DOPA-induced dyskinesia (LID) in the mouse, to compare the efficacy of several subtype-specific DAR antagonists (Paper II); (iii) applying cell type-specific chemogenetics to determine how the two main types of SPNs contribute to therapeutic vs. dyskinetic effects of L-DOPA (Paper IV). Our results reveal that L-DOPA-induced ERK1/2 depends on an interaction between D1R and calcium-dependent pathways, which are critically modulated by metabotropic glutamate receptor type 5 (mGluR5). Antagonizing mGluR5 or its downstream effectors, such as phospholipase C (PLC), inhibits striatal ERK1/2 activation both ex vivo and in vivo. Moreover, in vivo antagonism of mGluR5 and PLC reduces D1R-dependent AIMs in rat and mouse models of dyskinesia. The same treatments do not affect dyskinesia provoked by the stimulation of D2 receptors (D2R), which is supposed to depend on striatal neurons of the indirect pathway (D2R-expressing). To dissect the contribution of D1R- and D2R-expressing neurons to dyskinesia, we used viral vector-mediated chemogenetics. The results show that both cell types contribute to LID with opposite modulatory roles. Stimulation of D1R-expressing SPNs amplifies both L-DOPA therapeutic and dyskinetic action, while activation of D2R-expressing SPNs inhibits them. Induction of AIMs is promoted by the recruitment of signaling mechanisms that mimic D1R activation. However, maximally severe AIMs are reproduced by concomitant activation of both D1R- and D2R-expressing SPNs, thus underlying the concurrent role of both pathways in the development of LID. Through the use of a novel scale for rating AIMs in the mouse model of PD, we also unraveled the anti-dyskinetic potential of several DAR antagonists. We found that antagonism of D1R, D2R, D3R and D4R reduced L-DOPA-induced AIMs with a treatment-specific anti-dyskinetic profile, thus pointing to an involvement of all DARs in the modulation of LID. Taken together, the results included in this thesis provide new insights on the signaling pathways and neural circuits through which the dopaminergic treatment of PD affects motor behaviors. Moreover, the work in this thesis contributes to methodological advances to preclinical research on PD and LID. <br/>}},
author = {{Sebastianutto, Irene}},
isbn = {{978-91-7619-379-2}},
language = {{eng}},
publisher = {{Lund University: Faculty of Medicine}},
school = {{Lund University}},
title = {{Striatal signaling in the treatment of Parkinson's disease}},
url = {{https://lup.lub.lu.se/search/files/17313499/Webb_Irene_S_kappa.pdf}},
year = {{2016}},
}