期刊
BRAIN
卷 131, 期 -, 页码 3361-3379出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awn192
关键词
Parkinson's disease; transplantation; dyskinesia; dopamine; synapse
资金
- The Michael Stern Foundation
- The Orchard Foundation
- The Consolidated Anti-Aging Foundation
- The Harold and Ronna Cooper Family
- Fondo de Investigaciones Sanitarias (FIS) [CM06/0068]
- [P50NS39793]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [P50NS039793] Funding Source: NIH RePORTER
OFF-L-dopa dyskinesias have been a surprising side-effect of intrastriatal foetal ventral mesencephalic transplantation in patients with Parkinson's disease. It has been proposed that excessive and unregulated dopaminergic stimulation of host post-synaptic striatal neurons by the grafts could be responsible for these dyskinesias. To address this issue we transplanted foetal dopaminergic neurons from mice lacking the dopamine transporter (DATKO) or fromwild-type mice, into a rat model of Parkinson's disease and L-dopa-induced dyskinesias. Both wild-type and DATKO grafts reinnervated the host striatum to a similar extent, but DATKO grafts produced a greater and more diffuse increase in extra-cellular striatal dopamine levels. Interestingly, grafts containing wild-type dopaminergic neurons improved parkinsonian signs to a similar extent as DATKO grafts, but provided a more complete reduction of L-dopa induced dyskinesias. Neither DATKO nor wild-type grafts induced OFF-L-dopa dyskinesias. Behavioural and receptor autoradiography analyses demonstrated that DATKO grafts induced a greater normalization of striatal dopaminergic receptor supersensitivity than wild-type grafts. Both graft types induced a similar downregulation and normalization of PEnk and fosb/Dfosb in striatal neurons. In summary, DATKO grafts causing high and diffuse extra-cellular dompamine levels do not per se alter graft-induced recovery or produce OFF-L-dopa dyskinesias. Wild-type dopaminergic neurons appear to be the most effective neuronal type to restore function and reduce L-dopa-induced dyskinesias.
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