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

Summary, in English

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.

• Author: Patrick Aldrin-Kirk; Andreas Heuer; Gang Wang; Bengt Mattsson; Martin Lundblad; Malin Parmar; Tomas Björklund
• Department/s: StemTherapy: National Initiative on Stem Cells for Regenerative Therapy; MultiPark: Multidisciplinary research focused on Parkinson´s disease; Molecular Neuromodulation; Developmental and Regenerative Neurobiology; Neurobiology
• Publishing year: 2016-06-01
• Language: English
• Pages: 955-968
• Publication/Series: Neuron
• Volume: 90
• Issue: 5
• Links: http://dx.doi.org/10.1016/j.neuron.2016.04.017
• Document type: Journal article
• Publisher: Cell Press
• Topic: Neurosciences
• Status: Published
• Research group: Molecular Neuromodulation; Developmental and Regenerative Neurobiology; Neurobiology
• ISBN/ISSN/Other: ISSN: 0896-6273