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Neuron. 2016 Jun 1;90(5):955-68. doi: 10.1016/j.neuron.2016.04.017. Epub 2016 May 5.

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

Author information

1
Molecular Neuromodulation, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden; Wallenberg Neuroscience Center, Lund University, 221 84 Lund, Sweden.
2
Molecular Neuromodulation, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden; Wallenberg Neuroscience Center, Lund University, 221 84 Lund, Sweden; Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.
3
Wallenberg Neuroscience Center, Lund University, 221 84 Lund, Sweden; Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.
4
Molecular Neuromodulation, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden; Wallenberg Neuroscience Center, Lund University, 221 84 Lund, Sweden. Electronic address: tomas.bjorklund@med.lu.se.

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 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.

PMID:
27161524
PMCID:
PMC4893163
DOI:
10.1016/j.neuron.2016.04.017
[Indexed for MEDLINE]
Free PMC Article

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