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DREADD Modulation of Transplanted DA Neurons Reveals a Novel Parkinsonian Dyskinesia Mechanism Mediated by the Serotonin 5-HT6 Receptor

Aldrin-Kirk, Patrick LU ; Heuer, Andreas LU ; Wang, Gang LU ; Mattsson, Bengt LU ; Lundblad, Martin LU ; Parmar, Malin LU orcid and Björklund, Tomas LU orcid (2016) In Neuron 90(5). p.955-968
Abstract

Transplantation of DA neurons is actively pursued as a restorative therapy in Parkinson's disease (PD). Pioneering clinical trials using transplants of fetal DA neuroblasts have given promising results, although a number of patients have developed graft-induced dyskinesias (GIDs), and the mechanism underlying this troublesome side effect is still unknown. Here we have used a new model where the activity of the transplanted DA neurons can be selectively modulated using a bimodal chemogenetic (DREADD) approach, allowing either enhancement or reduction of the therapeutic effect. We show that exclusive activation of a cAMP-linked (Gs-coupled) DREADD or serotonin 5-HT6 receptor, located on the grafted DA neurons, is sufficient to induce... (More)

Transplantation of DA neurons is actively pursued as a restorative therapy in Parkinson's disease (PD). Pioneering clinical trials using transplants of fetal DA neuroblasts have given promising results, although a number of patients have developed graft-induced dyskinesias (GIDs), and the mechanism underlying this troublesome side effect is still unknown. Here we have used a new model where the activity of the transplanted DA neurons can be selectively modulated using a bimodal chemogenetic (DREADD) approach, allowing either enhancement or reduction of the therapeutic effect. We show that exclusive activation of a cAMP-linked (Gs-coupled) DREADD or serotonin 5-HT6 receptor, located on the grafted DA neurons, is sufficient to induce GIDs. These findings establish a mechanistic link between the 5-HT6 receptor, intracellular cAMP, and GIDs in transplanted PD patients. This effect is thought to be mediated through counteraction of the D2 autoreceptor feedback inhibition, resulting in a dysplastic DA release from the transplant.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Neuron
volume
90
issue
5
pages
14 pages
publisher
Cell Press
external identifiers
  • pmid:27161524
  • wos:000378523900010
  • scopus:84964928610
ISSN
0896-6273
DOI
10.1016/j.neuron.2016.04.017
language
English
LU publication?
yes
id
1304dee6-5532-4c6a-b5ff-6dc2cb44636e
date added to LUP
2016-07-25 13:56:03
date last changed
2025-01-11 09:31:48
@article{1304dee6-5532-4c6a-b5ff-6dc2cb44636e,
  abstract     = {{<p>Transplantation of DA neurons is actively pursued as a restorative therapy in Parkinson's disease (PD). Pioneering clinical trials using transplants of fetal DA neuroblasts have given promising results, although a number of patients have developed graft-induced dyskinesias (GIDs), and the mechanism underlying this troublesome side effect is still unknown. Here we have used a new model where the activity of the transplanted DA neurons can be selectively modulated using a bimodal chemogenetic (DREADD) approach, allowing either enhancement or reduction of the therapeutic effect. We show that exclusive activation of a cAMP-linked (Gs-coupled) DREADD or serotonin 5-HT6 receptor, located on the grafted DA neurons, is sufficient to induce GIDs. These findings establish a mechanistic link between the 5-HT6 receptor, intracellular cAMP, and GIDs in transplanted PD patients. This effect is thought to be mediated through counteraction of the D2 autoreceptor feedback inhibition, resulting in a dysplastic DA release from the transplant.</p>}},
  author       = {{Aldrin-Kirk, Patrick and Heuer, Andreas and Wang, Gang and Mattsson, Bengt and Lundblad, Martin and Parmar, Malin and Björklund, Tomas}},
  issn         = {{0896-6273}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{5}},
  pages        = {{955--968}},
  publisher    = {{Cell Press}},
  series       = {{Neuron}},
  title        = {{DREADD Modulation of Transplanted DA Neurons Reveals a Novel Parkinsonian Dyskinesia Mechanism Mediated by the Serotonin 5-HT6 Receptor}},
  url          = {{http://dx.doi.org/10.1016/j.neuron.2016.04.017}},
  doi          = {{10.1016/j.neuron.2016.04.017}},
  volume       = {{90}},
  year         = {{2016}},
}