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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 and Björklund, Tomas LU (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
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
  • 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
2016-09-20 03:06:18
@misc{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    = {ARRAY(0x7e53888)},
  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},
  volume       = {90},
  year         = {2016},
}