Striatal adaptations in experimental parkinsonism and L-DOPA-induced dyskinesia
Author
Summary, in English
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.
Department/s
Publishing year
2014
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2014:72
Document type
Dissertation
Publisher
Neurobiology, Lund University, Faculty of Medicine
Topic
- Neurosciences
Keywords
- Striatum
- Parkinson’s disease
- L-DOPA-induced dyskinesia
- ERK1/2
- mGluR5
- homeostatic plasticity
- SPN
- 2‑Photon microscopy
Status
Published
Research group
- Basal Ganglia Pathophysiology
Supervisor
- Angela Cenci Nilsson
- Anders Björklund
- Dalton James Surmeier
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-7619001-2
Defence date
4 June 2014
Defence time
10:00
Defence place
Segerfalksalen, Wallenberg Neuroscience Center, Lund, Sweden
Opponent
- Rosario Moratalla (Prof.)