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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Research Article Neuroscience

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 9

Electrophysiological response to CNO in DREADD-transduced dSPNs from intact and 6-OHDA–lesioned mice.

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Electrophysiological response to CNO in DREADD-transduced dSPNs from int...
Whole-cell patch clamp recordings were made in ex vivo slices from dSPNs transduced with hM3Dq (A, C, and E) or rM3Ds (B, D, and F). (A and B) Bath application of CNO (10 μM) gradually increased the number of APs induced by brief somatic current pulses. No differences were observed between dSPNs of intact and 6-OHDA–lesioned mice transduced with the hM3Dq construct, while the effect of CNO stimulation was greater in the presence of a lesion in rM3Ds-transduced mice. RM 2-way ANOVA (n = 7–8 cells per data set): (A) hM3Dq: effect of lesion, F(1, 13) = 0.001, P = 0.980; time (effect of CNO), F(5, 65) = 12.11, P < 0.001; interaction, F(5, 65) = 0.1870, P = 0.966. (B) rM3Ds: effect of lesion, F(1, 13) = 12.39, P = 0.0038; time (effect of CNO), F(5, 65) = 8.125, P < 0.0001; interaction, F(5, 65) = 1.885, P = 0.109. **P < 0.01 for the effect of the lesion comparing intact vs. 6-OHDA–lesioned mice. (C and D) Frequency of induced APs between baseline and CNO in intact and 6-OHDA–lesioned mice transduced with hM3Dq (C) and rM3Ds (D). Baseline and CNO refer to the average frequency of induced APs (Hz) during the first 5 minutes and the last 5 minutes of CNO bath application, respectively. Paired 2-tailed Student’s t test: *P < 0.05; **P < 0.01; ***P < 0.001 for baseline vs. CNO. (E and F) Representative traces of AP responses to current injection, at baseline and after CNO application, in hM3Dq- and rM3Ds-transduced dSPNs, respectively.