Serotonergic Neurons Mediate Dyskinesia Side Effects in Parkinson’s Patients with Neural Transplants

Two patients with Parkinson’s disease, successfully treated with fetal tissue transplants more than a decade ago, developed troublesome involuntary movements, which could be treated with a serotonin receptor agonist. The Two Faces of Fetal Grafts Before stem cells, there were fetal grafts. Pioneering treatments performed in the 1990s in patients with Parkinson’s disease proved that the diseased brain could be repaired, at least for a while. Two of these patients received grafts, one in the putamen and the other in both the caudate and the putamen, of fetal midbrain tissue. For several years, the patients showed mild improvement but eventually were able to function well with no drugs. Recently, however, both have started to experience abnormal uncontrolled movements, which Politis and colleagues have determined are a result of an overabundance of serotonin-using neurons that developed from the graft. A serotonin agonist eliminates these dyskinesias. Brain imaging exposed what was happening in these patients’ brains. When imaged by positron emission tomography, radioactive tracers that tag dopaminergic neurons and that bind to the dopamine receptor showed that the dopamine neurons that decay during Parkinson’s disease were restored by the grafts. Another scan with an agent that binds to the serotonin transporter showed an abnormality; there seemed to be more serotonin neurons than usual. This presented a conundrum because dyskinesias in Parkinson’s disease are thought to be a result of dopamine, not serotonin, stimulation. The authors hypothesized that the explanation lies in the ability of the serotonin neurons to switch to a different neurotransmitter—to adopt dopamine as a so-called false transmitter, releasing it to cause dyskinesias. If this were the case, then desensitizing these serotonin neurons, and so inhibiting their activity, would reduce the dyskinesias. They tested this idea by giving the patients low doses of a serotonin receptor agonist called buspirone. Both patients responded by a sudden and almost complete resolution of the troublesome abnormal movements, suggesting that the excess serotonergic neurons had in fact been pumping out dopamine, causing the dyskinesias. The patients described here are only two of a larger number who received fetal neural tissue implants years ago. In some patients, the grafted cells survived, possibly as a result of stem cells within the graft, and were able to replace the function of the diseased dopamine cells, forming connections with the existing brain cells. Exploration of the long-term consequences of such replacement tissue, such as the atypical movements and their inhibition reported here, is important in that it will inform future treatments with grafts that consist of cells from other sources, such as bioengineered or stem cells. Troublesome involuntary movements in the absence of dopaminergic medication, so-called off-medication dyskinesias, are a serious adverse effect of fetal neural grafts that hinders the development of cell-based therapies for Parkinson’s disease. The mechanisms underlying these dyskinesias are not well understood, and it is not known whether they are the same as in the dyskinesias induced by l-dopa treatment. Using in vivo brain imaging, we show excessive serotonergic innervation in the grafted striatum of two patients with Parkinson’s disease, who had exhibited major motor recovery after transplantation with dopamine-rich fetal mesencephalic tissue but had later developed off-medication dyskinesias. The dyskinesias were markedly attenuated by systemic administration of a serotonin [5-hydroxytryptamine (5-HT)] receptor (5-HT1A) agonist, which dampens transmitter release from serotonergic neurons, indicating that the dyskinesias were caused by the serotonergic hyperinnervation. Our observations suggest strategies for avoiding and treating graft-induced dyskinesias that result from cell therapies for Parkinson’s disease with fetal tissue or stem cells.