Neuronal and glial responses to dopaminergic denervation
(2024) In Lund University, Faculty of Medicine Doctoral Dissertation Series- Abstract
- Parkinson's disease (PD) is characterised by severe degeneration of dopamine (DA) neurons innervating the striatum. Spiny projection neurons (SPNs), are the principal type of striatal neuron and belong to either of two classes: the D2 receptor-positive indirect pathway SPNs (iSPNs) and the D1 receptor-positive direct pathway SPNs (dSPNs). The thesis aims at investigating dynamic changes of SPNs and the surrounding glial cells following the loss of dopaminergic innervation. Studies are performed in a mouse model where the toxin 6-hydroxydopamine (6-OHDA) is used to kill DA neurons projecting to the dorsolateral striatum. After establishing that at least 95% of striatal DA fibres are lost 5 days after 6-OHDA injection, we selected 5 and 28... (More)
- Parkinson's disease (PD) is characterised by severe degeneration of dopamine (DA) neurons innervating the striatum. Spiny projection neurons (SPNs), are the principal type of striatal neuron and belong to either of two classes: the D2 receptor-positive indirect pathway SPNs (iSPNs) and the D1 receptor-positive direct pathway SPNs (dSPNs). The thesis aims at investigating dynamic changes of SPNs and the surrounding glial cells following the loss of dopaminergic innervation. Studies are performed in a mouse model where the toxin 6-hydroxydopamine (6-OHDA) is used to kill DA neurons projecting to the dorsolateral striatum. After establishing that at least 95% of striatal DA fibres are lost 5 days after 6-OHDA injection, we selected 5 and 28 days post lesion (DPL) as representing early vs. chronic stages of DA denervation. Our results show that a loss of dendritic spines occurs in iSPNs already at 5 DPL whereas this process becomes significant in dSPNs only at 28 DPL. In both cell types the dendritic remodeling is accompanied by maladaptive changes in synaptic plasticity and intrinsic electrophysiological properties. We show that caspase-3 is strongly activated at 5 DPL and that a caspase inhibitor can prevent spine pruning and synaptic changes in iSPNs. In another study we show that DA denervation induces a strong transient activation of microglia followed by a sustained activation of astrocytes. This is accompanied by striatal upregulation of pro-inflammatory molecules. At 5 DPL, activated microglial cells form close contacts with SPN dendrites, and these contacts are significantly more abundant on iSPNs compared to dSPNs, suggesting that microglia are involved in the early pruning of iSPN spines. Finally, we show that the antidepressant drug fluvoxamine can partially protect DA neurons from the toxic damage while reducing microglial activation, an effect mediated by the Sigma-1 receptor. Our results shed new light on the coordinated dynamic changes taking place in neurons and glia following DA denervation and provide new clues of therapeutic importance. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/5de636d0-41fd-41e2-b6c9-5986df647384
- author
- Li, Chang LU
- supervisor
- opponent
-
- Professor Pekna, Marcela, Göteborgs Universitet, Institutionen för neurovetenskap och fysiologi
- organization
- publishing date
- 2024
- type
- Thesis
- publication status
- published
- subject
- keywords
- Parkinson’s disease (PD), 6-OHDA, Striatum, Dopamine, SPNs, dendritic regression, spine pruning, neuroinflammation, fluvoxamine, microglia, Neuroprotection, disease modifying treatment
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2024:93
- pages
- 92 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
- defense date
- 2024-09-24 13:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-588-6
- language
- English
- LU publication?
- yes
- id
- 5de636d0-41fd-41e2-b6c9-5986df647384
- date added to LUP
- 2024-09-03 23:54:21
- date last changed
- 2025-04-04 14:58:04
@phdthesis{5de636d0-41fd-41e2-b6c9-5986df647384,
abstract = {{Parkinson's disease (PD) is characterised by severe degeneration of dopamine (DA) neurons innervating the striatum. Spiny projection neurons (SPNs), are the principal type of striatal neuron and belong to either of two classes: the D2 receptor-positive indirect pathway SPNs (iSPNs) and the D1 receptor-positive direct pathway SPNs (dSPNs). The thesis aims at investigating dynamic changes of SPNs and the surrounding glial cells following the loss of dopaminergic innervation. Studies are performed in a mouse model where the toxin 6-hydroxydopamine (6-OHDA) is used to kill DA neurons projecting to the dorsolateral striatum. After establishing that at least 95% of striatal DA fibres are lost 5 days after 6-OHDA injection, we selected 5 and 28 days post lesion (DPL) as representing early vs. chronic stages of DA denervation. Our results show that a loss of dendritic spines occurs in iSPNs already at 5 DPL whereas this process becomes significant in dSPNs only at 28 DPL. In both cell types the dendritic remodeling is accompanied by maladaptive changes in synaptic plasticity and intrinsic electrophysiological properties. We show that caspase-3 is strongly activated at 5 DPL and that a caspase inhibitor can prevent spine pruning and synaptic changes in iSPNs. In another study we show that DA denervation induces a strong transient activation of microglia followed by a sustained activation of astrocytes. This is accompanied by striatal upregulation of pro-inflammatory molecules. At 5 DPL, activated microglial cells form close contacts with SPN dendrites, and these contacts are significantly more abundant on iSPNs compared to dSPNs, suggesting that microglia are involved in the early pruning of iSPN spines. Finally, we show that the antidepressant drug fluvoxamine can partially protect DA neurons from the toxic damage while reducing microglial activation, an effect mediated by the Sigma-1 receptor. Our results shed new light on the coordinated dynamic changes taking place in neurons and glia following DA denervation and provide new clues of therapeutic importance.}},
author = {{Li, Chang}},
isbn = {{978-91-8021-588-6}},
issn = {{1652-8220}},
keywords = {{Parkinson’s disease (PD); 6-OHDA; Striatum; Dopamine; SPNs; dendritic regression; spine pruning; neuroinflammation; fluvoxamine; microglia; Neuroprotection; disease modifying treatment}},
language = {{eng}},
number = {{2024:93}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Neuronal and glial responses to dopaminergic denervation}},
url = {{https://lup.lub.lu.se/search/files/194470212/Chang_Li_-_WEBB.pdf}},
year = {{2024}},
}