Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson's disease therapy
Standard
Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson's disease therapy. / Alcacer, Cristina; Andreoli, Laura; Sebastianutto, Irene; Jakobsson, Johan; Fieblinger, Tim; Cenci, Maria Angela.
in: J CLIN INVEST, Jahrgang 127, Nr. 2, 01.02.2017, S. 720-734.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson's disease therapy
AU - Alcacer, Cristina
AU - Andreoli, Laura
AU - Sebastianutto, Irene
AU - Jakobsson, Johan
AU - Fieblinger, Tim
AU - Cenci, Maria Angela
PY - 2017/2/1
Y1 - 2017/2/1
N2 - Parkinson's disease (PD) patients experience loss of normal motor function (hypokinesia), but can develop uncontrollable movements known as dyskinesia upon treatment with L-DOPA. Poverty or excess of movement in PD has been attributed to overactivity of striatal projection neurons forming either the indirect (iSPNs) or the direct (dSPNs) pathway, respectively. Here, we investigated the two pathways' contribution to different motor features using SPN type-specific chemogenetic stimulation in rodent models of PD (PD mice) and L-DOPA-induced dyskinesia (LID mice). Using the activatory Gq-coupled human M3 muscarinic receptor (hM3Dq), we found that chemogenetic stimulation of dSPNs mimicked, while stimulation of iSPNs abolished the therapeutic action of L-DOPA in PD mice. In LID mice, hM3Dq stimulation of dSPNs exacerbated dyskinetic responses to L-DOPA, while stimulation of iSPNs inhibited these responses. In the absence of L-DOPA, only chemogenetic stimulation of dSPNs mediated through the Gs-coupled modified rat muscarinic M3 receptor (rM3Ds) induced appreciable dyskinesia in PD mice. Combining D2 receptor agonist treatment with rM3Ds-dSPN stimulation reproduced all symptoms of LID. These results demonstrate that dSPNs and iSPNs oppositely modulate both therapeutic and dyskinetic responses to dopamine replacement therapy in PD. We also show that chemogenetic stimulation of different signaling pathways in dSPNs leads to markedly different motor outcomes. Our findings have important implications for the design of effective antiparkinsonian and antidyskinetic drug therapies.
AB - Parkinson's disease (PD) patients experience loss of normal motor function (hypokinesia), but can develop uncontrollable movements known as dyskinesia upon treatment with L-DOPA. Poverty or excess of movement in PD has been attributed to overactivity of striatal projection neurons forming either the indirect (iSPNs) or the direct (dSPNs) pathway, respectively. Here, we investigated the two pathways' contribution to different motor features using SPN type-specific chemogenetic stimulation in rodent models of PD (PD mice) and L-DOPA-induced dyskinesia (LID mice). Using the activatory Gq-coupled human M3 muscarinic receptor (hM3Dq), we found that chemogenetic stimulation of dSPNs mimicked, while stimulation of iSPNs abolished the therapeutic action of L-DOPA in PD mice. In LID mice, hM3Dq stimulation of dSPNs exacerbated dyskinetic responses to L-DOPA, while stimulation of iSPNs inhibited these responses. In the absence of L-DOPA, only chemogenetic stimulation of dSPNs mediated through the Gs-coupled modified rat muscarinic M3 receptor (rM3Ds) induced appreciable dyskinesia in PD mice. Combining D2 receptor agonist treatment with rM3Ds-dSPN stimulation reproduced all symptoms of LID. These results demonstrate that dSPNs and iSPNs oppositely modulate both therapeutic and dyskinetic responses to dopamine replacement therapy in PD. We also show that chemogenetic stimulation of different signaling pathways in dSPNs leads to markedly different motor outcomes. Our findings have important implications for the design of effective antiparkinsonian and antidyskinetic drug therapies.
KW - Animals
KW - Humans
KW - Levodopa/adverse effects
KW - Mice
KW - Mice, Transgenic
KW - Neural Pathways/metabolism
KW - Neurons/metabolism
KW - Parkinson Disease, Secondary/chemically induced
KW - Rats
KW - Receptor, Muscarinic M3/agonists
KW - Receptors, Dopamine D2/agonists
KW - Visual Cortex/metabolism
U2 - 10.1172/JCI90132
DO - 10.1172/JCI90132
M3 - SCORING: Journal article
C2 - 28112685
VL - 127
SP - 720
EP - 734
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 2
ER -