Striatal pathways in dyskinesia and dystonia
(2021) In Lund University, Faculty of Medicine Doctoral Dissertation Series- Abstract
- Purposeful and well-coordinated movements depend on the control exerted by dopamine (DA) on the basal ganglia (BG) network. Accordingly, dysfunctions or lesions of the dopaminergic system in the BG can result in an overall poverty and slowness of movement, cardinal features of Parkinson´s disease (PD), or in dyskinesias, exaggerated and involuntary movements resulting from L-DOPA pharmacotherapy.
The corpus striatum is the fulcrum of DA-dependent movement control. From this structure originate two pathways that are thought to modulate movement in opposite ways. The movement-promoting pathway (‘direct pathway’) originates from striatal projection neurons (dSPNs) expressing dopamine (DA) D1 receptors (D1Rs), whereas the... (More) - Purposeful and well-coordinated movements depend on the control exerted by dopamine (DA) on the basal ganglia (BG) network. Accordingly, dysfunctions or lesions of the dopaminergic system in the BG can result in an overall poverty and slowness of movement, cardinal features of Parkinson´s disease (PD), or in dyskinesias, exaggerated and involuntary movements resulting from L-DOPA pharmacotherapy.
The corpus striatum is the fulcrum of DA-dependent movement control. From this structure originate two pathways that are thought to modulate movement in opposite ways. The movement-promoting pathway (‘direct pathway’) originates from striatal projection neurons (dSPNs) expressing dopamine (DA) D1 receptors (D1Rs), whereas the movement-suppressing pathway (‘indirect pathway’) originates from striatal neurons (iSPNs) expressing D2 receptors (D2R).
Classic theories attribute L-DOPA-induced dyskinesia (LID) to the overactivity of the movement-promoting pathway resulting from an aberrant activation of dSPN-D1R-mediated signalling in the DA-denervated striatum. However, these theories are inadequate to explain the complexity of LID, which cannot simply be equated with “more movement”, but instead consists of a mixture of fast hyperkinetic motions and dystonic postures in varying combinations. The overarching aim of this thesis is to parse the involvement of striatal output pathways and DA receptor subtypes in treatment-induced dyskinesia and dystonia using rodent models of clinically manifest PD.
Using pathway-specific chemogenetic modulation, we demonstrate that selective iSPN stimulation promotes hypokinesia and inhibits the dyskinetic action of L-DOPA, while dSPN stimulation has opposite effects. Moreover, we prove that dSPN stimulation alone can induce mild dyskinesia, though not the full spectrum and severity of LID. In a second study, we show that D1Rs and metabotropic glutamate receptors type 5 form heteromers in the DA-denervated striatum, and that these receptor interactions are causally linked with dyskinesias mediated by D1R stimulation. Next, using a set of pharmacological tools and models of gene receptor ablation we show that D1R and D2R stimulation mediate different forms of dyskinesia. Specifically, D1R activation elicits mainly the hyperkinetic components of LID, whereas the D2R mediate mainly its dystonic features.
Taken together, the results of this thesis present a refinement of the pathophysiological notions regarding the contribution of striatal pathways to the motor features of PD and LID, paving the way for more effective treatment options. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/e51554f5-d2cc-4378-b1c7-22e3accefa12
- author
- Andreoli, Laura LU
- supervisor
- opponent
-
- professor Moratalla, Rosario, Cajal Institute, Consejo Superior de Investigationes Cientificas (CSIC), Madrid, Spain
- organization
- publishing date
- 2021
- type
- Thesis
- publication status
- published
- subject
- keywords
- Striatum, Dystonia, L-DOPA-induced dyskinesia, DREADD, Mouse model, Dopamine, dopamine receptor
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2021:146
- publisher
- Lund University, Faculty of Medicine
- defense location
- Segerfalksalen, BMC A10, Sölvegatan 17 i Lund. Join by Zoom: https://lu-se.zoom.us/j/61300229294?pwd=Z2JxNWdqczQ1SWNUNDZjN1hRVmlWdz09
- defense date
- 2021-12-14 13:30:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-153-6
- language
- English
- LU publication?
- yes
- id
- e51554f5-d2cc-4378-b1c7-22e3accefa12
- date added to LUP
- 2021-11-08 16:23:00
- date last changed
- 2022-06-29 09:17:04
@phdthesis{e51554f5-d2cc-4378-b1c7-22e3accefa12,
abstract = {{Purposeful and well-coordinated movements depend on the control exerted by dopamine (DA) on the basal ganglia (BG) network. Accordingly, dysfunctions or lesions of the dopaminergic system in the BG can result in an overall poverty and slowness of movement, cardinal features of Parkinson´s disease (PD), or in dyskinesias, exaggerated and involuntary movements resulting from L-DOPA pharmacotherapy.<br/>The corpus striatum is the fulcrum of DA-dependent movement control. From this structure originate two pathways that are thought to modulate movement in opposite ways. The movement-promoting pathway (‘direct pathway’) originates from striatal projection neurons (dSPNs) expressing dopamine (DA) D1 receptors (D1Rs), whereas the movement-suppressing pathway (‘indirect pathway’) originates from striatal neurons (iSPNs) expressing D2 receptors (D2R).<br/>Classic theories attribute L-DOPA-induced dyskinesia (LID) to the overactivity of the movement-promoting pathway resulting from an aberrant activation of dSPN-D1R-mediated signalling in the DA-denervated striatum. However, these theories are inadequate to explain the complexity of LID, which cannot simply be equated with “more movement”, but instead consists of a mixture of fast hyperkinetic motions and dystonic postures in varying combinations. The overarching aim of this thesis is to parse the involvement of striatal output pathways and DA receptor subtypes in treatment-induced dyskinesia and dystonia using rodent models of clinically manifest PD.<br/>Using pathway-specific chemogenetic modulation, we demonstrate that selective iSPN stimulation promotes hypokinesia and inhibits the dyskinetic action of L-DOPA, while dSPN stimulation has opposite effects. Moreover, we prove that dSPN stimulation alone can induce mild dyskinesia, though not the full spectrum and severity of LID. In a second study, we show that D1Rs and metabotropic glutamate receptors type 5 form heteromers in the DA-denervated striatum, and that these receptor interactions are causally linked with dyskinesias mediated by D1R stimulation. Next, using a set of pharmacological tools and models of gene receptor ablation we show that D1R and D2R stimulation mediate different forms of dyskinesia. Specifically, D1R activation elicits mainly the hyperkinetic components of LID, whereas the D2R mediate mainly its dystonic features.<br/>Taken together, the results of this thesis present a refinement of the pathophysiological notions regarding the contribution of striatal pathways to the motor features of PD and LID, paving the way for more effective treatment options.}},
author = {{Andreoli, Laura}},
isbn = {{978-91-8021-153-6}},
issn = {{1652-8220}},
keywords = {{Striatum; Dystonia; L-DOPA-induced dyskinesia; DREADD; Mouse model; Dopamine; dopamine receptor}},
language = {{eng}},
number = {{2021:146}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Striatal pathways in dyskinesia and dystonia}},
url = {{https://lup.lub.lu.se/search/files/109448300/Laura_Andreoli_web.pdf}},
year = {{2021}},
}