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Striatal adaptations in experimental parkinsonism and L-DOPA-induced dyskinesia

Fieblinger, Tim LU (2014) In Lund University, Faculty of Medicine Doctoral dissertation Series 2014:72.
Abstract (Swedish)
Abstract in German

Die Parkinson-Krankheit („Parkinson”) ist eine neurodegenerative Erkrankung die durch den Verlust von Dopamin-produzierenden Nervenzellen in der Substantia Nigra und daraus resultierenden, typischen motorischen Symptomen gekennzeichnet ist. Die Standardbehandlung für Parkinson ist die Gabe von L-DOPA, zum Zweck der Ersetzung des verlorengegangen Dopamins. Eine Langzeittherapie mit L-DOPA führt jedoch häufig zu schweren Nebenwirkungen, in Form von unfreiwilligen und abnormalen Bewegungen, den sogenannten L-DOPA induzierten Dyskinesien (LID). Die Ätiologie beider motorischer Krankheitsbilder ist größtenteils unbekannt, jedoch ist Dopamin ein gemeinsamer Nenner. Die Veränderungen von Nervenzellen in einer... (More)
Abstract in German

Die Parkinson-Krankheit („Parkinson”) ist eine neurodegenerative Erkrankung die durch den Verlust von Dopamin-produzierenden Nervenzellen in der Substantia Nigra und daraus resultierenden, typischen motorischen Symptomen gekennzeichnet ist. Die Standardbehandlung für Parkinson ist die Gabe von L-DOPA, zum Zweck der Ersetzung des verlorengegangen Dopamins. Eine Langzeittherapie mit L-DOPA führt jedoch häufig zu schweren Nebenwirkungen, in Form von unfreiwilligen und abnormalen Bewegungen, den sogenannten L-DOPA induzierten Dyskinesien (LID). Die Ätiologie beider motorischer Krankheitsbilder ist größtenteils unbekannt, jedoch ist Dopamin ein gemeinsamer Nenner. Die Veränderungen von Nervenzellen in einer Dopamin-empfänglichen Gehirnregion bei Parkinson und LID ist Gegenstand der vorliegenden Dissertation.

Das Striatum gehört zu den Basalganglien, welche in die Steuerung von Bewegungen eingebunden sind. Die Hauptnervenzellen im Striatum sind in zwei Populationen unterteilt und bilden den sogenannten direkten und indirekten Projektionsweg der Basalganglien. Diese zwei Populationen werden aufgrund unterschiedlicher Ausstattung mit Dopamin-Rezeptoren gegensätzlich von Dopamin moduliert.

Die Stimulierung des D1 Rezeptors im parkinsonoiden Striatum führt zu einer super-sensiblen Aktivierung der Kinasen ERK1/2. Man nimmt weitestgehend an das diese abnormale Signalaktivierung einen Kernmechanismus für die Entwicklung von LID darstellt. In der ersten Studie haben wir daher untersucht, welche Signalwege an der D1 Rezeptor-induzierten ERK1/2 Aktivierung beteiligt sind. Wir konnten eine komplexe Interaktion von PKA- und Calcium-abhängigen Signalwegen aufzeigen, welche zudem maßgeblich von mGluR5 moduliert wird. In der zweiten Studie haben wird daraufhin das anti-dyskinetische Profil der Behandlung mit einem mGluR5 Antagonisten charakterisiert. Es zeigte sich, dass die Wahl des Tiermodelles einen kritischen Einfluss auf das Ergebnis der antidyskinetischen Therapie hat. Jene Veränderungen von Zellen im Striatum, welche eine nützliche Blockierung von mGluR5 möglich machen, sind in Tiermodellen mit teilweiser Dopamin Denervierung nur unzureichend vorhanden.

In der letzten Studie untersuchten wir homeostatische Mechanismen in striatalen Nervenzellen bei Parkinson und LID. Beide Populationen zeigten homeostatische Anpassungen von zellulärer Erregbarkeit, als mögliche Gegenmaßnahme zum Verlust von Dopamin und zur Erlangung eines Ausgleiches der neuronalen Feueraktivität. Diese Anpassungen waren gegensätzlich gerichtet in den Populationen. Eine Atrophie von Dendriten war im Gegensatz dazu jedoch gleichermaßen in beiden Populationen zu finden und scheint daher dopaminunabhängig zu sein. Weitere Anpassungen von Synapsen bei Parkinson und LID folgten nicht den homeostatischen Regeln. Im Besonderen konnten wir keine Skalierung der synaptischen Stärken beobachten, sondern vielmehr eine selektive Eliminierung von Synapsen. Dies legt die Vermutung nahe, dass striatale Nervenzellen bei Parkinson und LID nicht in der Lage sind die Funktion der Basalganglien angemessen zu regulieren.

Die Anpassungen im Striatum sind ein wichtiger Faktor bei beiden Krankheitszuständen. Hierbei ist es schwer, kompensatorische von fehlgeleiteten Anpassungen zu unterscheiden. Je mehr Wissen wir jedoch über diese erlangen, desto besser können wir Tiermodelle optimieren und potenzielle Therapieoptionen für Parkinson und LID identifizieren. (Less)
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder, characterized by the loss of dopamine (DA) producing neurons in the substantia nigra pars compacta (SNc), resulting in typical motor symptoms. DA replacement with L-DOPA is the standard therapy for PD. However, with treatment duration many patients face the severe treatment complication of L-DOPA-induced dyskinesia (LID), constituting in abnormal involuntary movements (AIMs). The etiology of PD and LID is largely unknown, but both pathophysiological states are linked to DA. How neurons in a DA-receptive brain region adapt to the pathophysiological states of PD and LID is the topic of this thesis’ work.

The striatum is the “hub” into the basal ganglia network and implicated... (More)
Parkinson’s disease (PD) is a neurodegenerative disorder, characterized by the loss of dopamine (DA) producing neurons in the substantia nigra pars compacta (SNc), resulting in typical motor symptoms. DA replacement with L-DOPA is the standard therapy for PD. However, with treatment duration many patients face the severe treatment complication of L-DOPA-induced dyskinesia (LID), constituting in abnormal involuntary movements (AIMs). The etiology of PD and LID is largely unknown, but both pathophysiological states are linked to DA. How neurons in a DA-receptive brain region adapt to the pathophysiological states of PD and LID is the topic of this thesis’ work.

The striatum is the “hub” into the basal ganglia network and implicated in movement control. Striatal spiny projection neurons (SPNs) divide into two subpopulations, forming the so-called direct and indirect pathway of the basal ganglia. Due to the expression of different DA receptors, direct and indirect pathway SPNs (dSPNs and iSPNs, respectively) are oppositely modulated by DA.

D1 receptor (D1R) stimulation in the DA-denervated, parkinsonian striatum leads to a supersensitive activation of ERK1/2 in dSPNs. This aberrant signaling activation is widely believed to be a core mechanism leading to the development of LID. In the first study we investigated which signaling pathways participate in this D1R-induced ERK1/2 activation. We found a distinct and complex interaction between PKA- and Ca2+-dependent pathways, which is critically modulated by mGluR5. In the second study we further investigated the antidsykinetic profile of mGluR5 antagonist treatment, finding that the choice of animal model influences the outcome of antidyskinetic therapy testing. Striatal adaptations, sensitive to beneficial mGluR5 inhibition, appear not to be represented in only partially DA-denervated animals.

In the last study we investigated possible homeostatic mechanisms in SPNs during PD and LID. We found that both iSPNs and dSPNs display potential homeostatic adaptations of excitability that are likely to counteract the loss of DA signaling and balance perturbations in firing activity. The changes were oppositely directed in iSPNs and dSPNs, reflecting the bidirectional modulation by DA. In contrast, PD-associated dendritic atrophy was found in both subpopulations and is independent of DAergic signaling. Synaptic adaptations in SPNs in PD and LID appeared not to follow homeostatic ruling. Specifically, we found that SPNs do not exhibit synaptic scaling, but rather selective elimination of spines. The failure to preserve the pattern of weighted synaptic inputs suggests that SPNs may not be able to appropriately regulate basal ganglia related behavior in PD and LID.

Taken together, the results of this thesis reveal new molecular and physiological adaptations of SPNs in experimental models of PD and LID. Identifying if they are compensatory or maladaptive is difficult, but the more our understanding proceeds the better we can refine preclinical animal models and define potential treatment options for PD and LID. (Less)
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author
supervisor
opponent
  • Prof. Moratalla, Rosario, Cajal Institute, CSIC, Madrid, Spain
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Striatum, Parkinson’s disease, L-DOPA-induced dyskinesia, ERK1/2, mGluR5, homeostatic plasticity, SPN, 2‑Photon microscopy
in
Lund University, Faculty of Medicine Doctoral dissertation Series
volume
2014:72
pages
134 pages
publisher
Neurobiology, Lund University, Faculty of Medicine
defense location
Segerfalksalen, Wallenberg Neuroscience Center, Lund, Sweden
defense date
2014-06-04 10:00
ISSN
1652-8220
ISBN
978-91-7619001-2
language
English
LU publication?
yes
id
f5d30aa8-9496-4582-a59d-00f0fc7a4ec2 (old id 4434858)
date added to LUP
2014-05-07 11:40:23
date last changed
2016-09-19 08:44:45
@phdthesis{f5d30aa8-9496-4582-a59d-00f0fc7a4ec2,
  abstract     = {Parkinson’s disease (PD) is a neurodegenerative disorder, characterized by the loss of dopamine (DA) producing neurons in the substantia nigra pars compacta (SNc), resulting in typical motor symptoms. DA replacement with L-DOPA is the standard therapy for PD. However, with treatment duration many patients face the severe treatment complication of L-DOPA-induced dyskinesia (LID), constituting in abnormal involuntary movements (AIMs). The etiology of PD and LID is largely unknown, but both pathophysiological states are linked to DA. How neurons in a DA-receptive brain region adapt to the pathophysiological states of PD and LID is the topic of this thesis’ work.<br/><br>
The striatum is the “hub” into the basal ganglia network and implicated in movement control. Striatal spiny projection neurons (SPNs) divide into two subpopulations, forming the so-called direct and indirect pathway of the basal ganglia. Due to the expression of different DA receptors, direct and indirect pathway SPNs (dSPNs and iSPNs, respectively) are oppositely modulated by DA.<br/><br>
D1 receptor (D1R) stimulation in the DA-denervated, parkinsonian striatum leads to a supersensitive activation of ERK1/2 in dSPNs. This aberrant signaling activation is widely believed to be a core mechanism leading to the development of LID. In the first study we investigated which signaling pathways participate in this D1R-induced ERK1/2 activation. We found a distinct and complex interaction between PKA- and Ca2+-dependent pathways, which is critically modulated by mGluR5. In the second study we further investigated the antidsykinetic profile of mGluR5 antagonist treatment, finding that the choice of animal model influences the outcome of antidyskinetic therapy testing. Striatal adaptations, sensitive to beneficial mGluR5 inhibition, appear not to be represented in only partially DA-denervated animals.<br/><br>
In the last study we investigated possible homeostatic mechanisms in SPNs during PD and LID. We found that both iSPNs and dSPNs display potential homeostatic adaptations of excitability that are likely to counteract the loss of DA signaling and balance perturbations in firing activity. The changes were oppositely directed in iSPNs and dSPNs, reflecting the bidirectional modulation by DA. In contrast, PD-associated dendritic atrophy was found in both subpopulations and is independent of DAergic signaling. Synaptic adaptations in SPNs in PD and LID appeared not to follow homeostatic ruling. Specifically, we found that SPNs do not exhibit synaptic scaling, but rather selective elimination of spines. The failure to preserve the pattern of weighted synaptic inputs suggests that SPNs may not be able to appropriately regulate basal ganglia related behavior in PD and LID.<br/><br>
Taken together, the results of this thesis reveal new molecular and physiological adaptations of SPNs in experimental models of PD and LID. Identifying if they are compensatory or maladaptive is difficult, but the more our understanding proceeds the better we can refine preclinical animal models and define potential treatment options for PD and LID.},
  author       = {Fieblinger, Tim},
  isbn         = {978-91-7619001-2},
  issn         = {1652-8220},
  keyword      = {Striatum,Parkinson’s disease,L-DOPA-induced dyskinesia,ERK1/2,mGluR5,homeostatic plasticity,SPN,2‑Photon microscopy},
  language     = {eng},
  pages        = {134},
  publisher    = {Neurobiology, Lund University, Faculty of Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral dissertation Series},
  title        = {Striatal adaptations in experimental parkinsonism and L-DOPA-induced dyskinesia},
  volume       = {2014:72},
  year         = {2014},
}