Editors' ChoiceNeuroscience

Paths to dyskinesia from nerve cell replacement

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Science Signaling  14 Jun 2016:
Vol. 9, Issue 432, pp. ec139
DOI: 10.1126/scisignal.aag2876

Neurodegenerative diseases involve the loss of specific neurons, which compromises various brain functions. In Parkinson’s disease, dopaminergic (DA) neurons of the substantia nigra die, causing uncontrollable movement. Strategies to restore these neurons by transplantation have met with some success, but some patients develop graft-induced dyskinesia (GID). Aldrin-Kirk et al. transplanted fetal rat DA neurons into a rat model of Parkinson’s disease, then used adenoviruses to introduce various combinations of DREADDs (designer receptors exclusively activated by designer drugs) to either increase or decrease dopamine released from the grafted tissue. Activation of Gq- or Gs-coupled DREADDs (hM3Dq or rM3Ds, both responding to CNO) enhanced dopamine release, whereas activation of a Gi-coupled DREADD [KORD, which responds to salvinorin B (SalB)] reduced dopamine release and blocked the effect of CNO. Although CNO administration improved motor behavior in the grafted rats expressing hM3Dq and rM3Ds or rM3Ds alone, these animals developed GID. GID did not occur in rats expressing hM3Dq and KORD, suggesting that Gs signaling is responsible for GID. The serotonin receptors 5-HT4, 5-HT5, and 5-HT6 are Gs-coupled receptors implicated in GID, and administration of receptor-specific agonists to the rats expressing hM3Dq and KORD showed that 5-HT6 stimulation resulted in aberrant behaviors similar to those induced by CNO. Local administration of the 5-HT6 agonist produced an electrophysiological response in the transplanted neurons similar to that produced by local CNO application in the hM3Dq and KORD-expressing animals. Staining of the transplanted tissue showed that a subset of the DA neurons was positive for 5-HT6 and that the transplant and surrounding striatum were innervated by serotonin-releasing neurons (positive for the serotonin transporter SERT). Transplants of dissociated human fetal ventral mesencephalon or human embryonic stem cells in immunosuppressed rats showed that 5-HT6 was abundant in the DA neurons of the transplanted tissue. Postmortem analysis of the brain of a human patient that received a human fetal ventral mesencephalon graft also revealed high abundance of 5-HT6 in the transplanted tissue. Thus, chemogenetic manipulation of neuronal activity through designer G protein–coupled receptors identified a pathway that could be targeted to improve the transplantation success for Parkinson’s disease patients.

P. Aldrin-Kirk, A. Heuer, G. Wang, B. Mattsson, M. Lundblad, M. Parmar, T. Björklund, DREADD modulation of transplanted DA neurons reveals a novel parkinsonian dyskinesia mechanism mediated by the serotonin 5-HT6 receptor. Neuron 90, 955–968 (2016). [PubMed]

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