Abstract
SummaryTransplantation 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.
Highlights
Restorative therapies based on nerve cell replacement, from extrinsic or intrinsic sources, have seen significant advances over the past decade
While some grafted patients have displayed substantial long-term clinical benefit from the dopaminergic cell transplants placed in the caudate/putamen (Kefalopoulou et al, 2014), the outcome has been highly variable (Barker et al, 2013), and a significant number of patients have developed abnormal involuntary movements induced by the graft
We found that increase of cyclic AMP in the grafted DA neurons, obtained through activation of the metabotropic Gscoupled DREADD, is sufficient to induce significant graft-induced dyskinesias (GIDs) in animals in the absence of any L-DOPA treatment
Summary
Restorative therapies based on nerve cell replacement, from extrinsic or intrinsic sources, have seen significant advances over the past decade. While some grafted patients have displayed substantial long-term clinical benefit from the dopaminergic cell transplants placed in the caudate/putamen (Kefalopoulou et al, 2014), the outcome has been highly variable (Barker et al, 2013), and a significant number of patients have developed abnormal involuntary movements induced by the graft (graft-induced dyskinesias, or GID). This troublesome side effect, seen in the absence of any drug treatment, has so far not been possible to reproduce in rodent or primate models of PD. The main reason for this is due to the fact that all attempts to reproduce this side effect in an authentic and clinically relevant animal model have so far failed
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