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Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson's disease therapy

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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, Vol. 127, No. 2, 01.02.2017, p. 720-734.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Alcacer, C, Andreoli, L, Sebastianutto, I, Jakobsson, J, Fieblinger, T & Cenci, MA 2017, 'Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson's disease therapy', J CLIN INVEST, vol. 127, no. 2, pp. 720-734. https://doi.org/10.1172/JCI90132

APA

Alcacer, C., Andreoli, L., Sebastianutto, I., Jakobsson, J., Fieblinger, T., & Cenci, M. A. (2017). Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson's disease therapy. J CLIN INVEST, 127(2), 720-734. https://doi.org/10.1172/JCI90132

Vancouver

Alcacer C, Andreoli L, Sebastianutto I, Jakobsson J, Fieblinger T, Cenci MA. Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson's disease therapy. J CLIN INVEST. 2017 Feb 1;127(2):720-734. https://doi.org/10.1172/JCI90132

Bibtex

@article{3ff713110faa4cabacdf87300c5dc473,
title = "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.",
keywords = "Animals, Humans, Levodopa/adverse effects, Mice, Mice, Transgenic, Neural Pathways/metabolism, Neurons/metabolism, Parkinson Disease, Secondary/chemically induced, Rats, Receptor, Muscarinic M3/agonists, Receptors, Dopamine D2/agonists, Visual Cortex/metabolism",
author = "Cristina Alcacer and Laura Andreoli and Irene Sebastianutto and Johan Jakobsson and Tim Fieblinger and Cenci, {Maria Angela}",
year = "2017",
month = feb,
day = "1",
doi = "10.1172/JCI90132",
language = "English",
volume = "127",
pages = "720--734",
journal = "J CLIN INVEST",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "2",

}

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 -