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

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Alcacer, CristinaLund University,Lunds universitet,Basala gangliernas patofysiologi,Forskargrupper vid Lunds universitet,Basal Ganglia Pathophysiology,Lund University Research Groups (author)

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

Article/chapterEnglish2017

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2017
15 s.

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LIBRIS-ID:oai:lup.lub.lu.se:60fb9690-81ce-4794-b1d2-c5d97dd189a1
https://lup.lub.lu.se/record/60fb9690-81ce-4794-b1d2-c5d97dd189a1URI
https://doi.org/10.1172/JCI90132DOI

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Language:English
Summary in:English

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Subject category:ref swepub-contenttype

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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.

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Andreoli, LauraLund University,Lunds universitet,Basala gangliernas patofysiologi,Forskargrupper vid Lunds universitet,Basal Ganglia Pathophysiology,Lund University Research Groups(Swepub:lu)med-lad (author)
Sebastianutto, IreneLund University,Lunds universitet,Basala gangliernas patofysiologi,Forskargrupper vid Lunds universitet,Basal Ganglia Pathophysiology,Lund University Research Groups(Swepub:lu)med-isi (author)
Jakobsson, JohanLund University,Lunds universitet,Molekylär neurogenetik,Forskargrupper vid Lunds universitet,Molecular Neurogenetics,Lund University Research Groups(Swepub:lu)mphy-jja (author)
Fieblinger, TimLund University,Lunds universitet,Basala gangliernas patofysiologi,Forskargrupper vid Lunds universitet,Basal Ganglia Pathophysiology,Lund University Research Groups(Swepub:lu)med-tfr (author)
Cenci Nilsson, AngelaLund University,Lunds universitet,Basala gangliernas patofysiologi,Forskargrupper vid Lunds universitet,Basal Ganglia Pathophysiology,Lund University Research Groups(Swepub:lu)mphy-ace (author)
Basala gangliernas patofysiologiForskargrupper vid Lunds universitet (creator_code:org_t)

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In:Journal of Clinical Investigation127:2, s. 720-7340021-9738

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