Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson’s disease therapy
Cristina Alcacer, … , Tim Fieblinger, Maria Angela Cenci
Cristina Alcacer, … , Tim Fieblinger, Maria Angela Cenci
Published January 23, 2017
Citation Information: J Clin Invest. 2017;127(2):720-734. https://doi.org/10.1172/JCI90132.
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Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson’s disease therapy

Abstract

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.

Authors

Cristina Alcacer, Laura Andreoli, Irene Sebastianutto, Johan Jakobsson, Tim Fieblinger, Maria Angela Cenci

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Figure 6

Induction of dyskinetic behaviors by Gq- versus Gs-DREADD–dependent activation of dSPNs in L-DOPA–naive 6-OHDA–lesioned mice.

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Induction of dyskinetic behaviors by Gq- versus Gs-DREADD–dependent acti...
(A and B) Bar diagrams show the total AIM score per session and the separate axial, limb, and orofacial scores following treatment with the lowest and highest doses of CNO tested in this experiment (1 and 5 mg/kg, respectively; see horizontal captions). Gray-shaded areas represent the range (mean ± SEM) of AIM scores induced by a therapeutic dose of L-DOPA (3 mg/kg) in D1-Cre 6-OHDA–lesioned mice (cf. Figure 5D). Data are shown as mean + SEM from n = 7 mice transduced with hM3Dq and n = 8 mice transduced with rM3Ds. Paired 2-tailed Student’s t test: *P < 0.05; **P < 0.01; ***P < 0.001 for CNO 5 mg/kg vs. CNO 1 mg/kg. (C and D) Direct comparisons of CNO-induced AIMs in mice transduced with the 2 different types of DREADD. (C and D) Time course of AIMs after CNO injection (scored every 20 minutes until 180 minutes). Two-way RM ANOVA: (C) CNO (1 mg/kg): DREADD type, F(1, 13) = 6.737, P < 0.05; time, F(8, 104) = 3.557, P < 0.01; interaction, F(8, 104) = 3.557, P < 0.001. (D) CNO (5 mg/kg): DREADD type F(1, 15) = 4.352, P = 0.054; time, F(8, 120) = 7.903, P < 0.001; interaction, F(8, 120) = 6.549, P < 0.001. Bar diagrams show the sum of AIM scores per session, and scores accrued on each of axial, limb, and orofacial AIMs are represented using different shades of gray. Unpaired 2-tailed Student’s t test: total AIMs per session: #P < 0.05; ##P < 0.01 vs. hM3Dq. Individual AIM subtypes: *P < 0.05; **P < 0.01 vs. hM3Dq.