Striatal pathways in dyskinesia and dystonia
Author
Summary, in English
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.
Department/s
Publishing year
2021
Language
English
Publication/Series
Lund University, Faculty of Medicine Doctoral Dissertation Series
Issue
2021:146
Full text
Document type
Dissertation
Publisher
Lund University, Faculty of Medicine
Topic
- Neurosciences
Keywords
- Striatum
- Dystonia
- L-DOPA-induced dyskinesia
- DREADD
- Mouse model
- Dopamine
- dopamine receptor
Status
Published
Research group
- Basal Ganglia Pathophysiology
Supervisor
- Angela Cenci Nilsson
- Cristina Alcacer
- Andreas Heuer
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-8021-153-6
Defence date
14 December 2021
Defence time
13:30
Defence place
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund. Join by Zoom: https://lu-se.zoom.us/j/61300229294?pwd=Z2JxNWdqczQ1SWNUNDZjN1hRVmlWdz09
Opponent
- Rosario Moratalla (professor)