title: DREADD Modulation of Transplanted DA Neurons Reveals a Novel Parkinsonian Dyskinesia Mechanism Mediated by the Serotonin 5-HT6 Receptor.
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.
authors.affiliation: Molecular Neuromodulation, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden; Wallenberg Neuroscience Center, Lund University, 221 84 Lund, Sweden.
authors.forename: Patrick
authors.initials: P
authors.lastname: Aldrin-Kirk
authors.affiliation: 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.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heuer
authors.affiliation: Molecular Neuromodulation, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden; Wallenberg Neuroscience Center, Lund University, 221 84 Lund, Sweden.
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Bengt
authors.initials: B
authors.lastname: Mattsson
authors.affiliation: Wallenberg Neuroscience Center, Lund University, 221 84 Lund, Sweden; Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Lundblad
authors.affiliation: Wallenberg Neuroscience Center, Lund University, 221 84 Lund, Sweden; Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Parmar
authors.affiliation: 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.
authors.forename: Tomas
authors.initials: T
authors.lastname: Björklund
mesh_terms: D000818:Animals; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology; D045785:Diterpenes, Clerodane; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation*; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology*; D005021:Ethylamines / Q000494:pharmacology; D005260:Female; D016332:Fetal Tissue Transplantation / Q000009:adverse effects*; D055879:Gene Knock-In Techniques; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000601:surgery; D011183:Postoperative Complications; D051381:Rats; D011985:Receptors, Serotonin / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*
chemical_list: C558115:2-(5-chloro-2-methyl-1H-indol-3-yl)-N,N-dimethylethanamine; D004224:Diterpenes; D045785:Diterpenes, Clerodane; D005021:Ethylamines; D007211:Indoles; D011985:Receptors, Serotonin; C508456:salvinorin B; C097216:serotonin 6 receptor; D016627:Oxidopamine; D000242:Cyclic AMP; D003024:Clozapine; C079149:clozapine N-oxide; D004298:Dopamine