Dysfunctional and compensatory synaptic plasticity in Parkinson's disease.

NEUROPLASTICITY; PARKINSON'S disease patients; DOPAMINERGIC neurons; MOTOR ability; BASAL ganglia diseases; PATHOLOGICAL physiology; COMPUTATIONAL biology; EMPIRICAL research

In Parkinson's disease, a loss of dopamine neurons causes severe motor impairments. These motor impairments have long been thought to result exclusively from immediate effects of dopamine loss on neuronal firing in basal ganglia, causing imbalances of basal ganglia pathways. However, motor impairments and pathway imbalances may also result from dysfunctional synaptic plasticity - a novel concept of how Parkinsonian symptoms evolve. Here we built a neuro-computational model that allows us to simulate the effects of dopamine loss on synaptic plasticity in basal ganglia. Our simulations confirm that dysfunctional synaptic plasticity can indeed explain the emergence of both motor impairments and pathway imbalances in Parkinson's disease, thus corroborating the novel concept. By predicting that dysfunctional plasticity results not only in reduced activation of desired responses, but also in their active inhibition, our simulations provide novel testable predictions. When simulating dopamine replacement therapy (which is a standard treatment in clinical practice), we observe a new balance of pathway outputs, rather than a simple restoration of non-Parkinsonian states. In addition, high doses of replacement are shown to result in overshooting motor activity, in line with empirical evidence. Finally, our simulations provide an explanation for the intensely debated paradox that focused basal ganglia lesions alleviate Parkinsonian symptoms, but do not impair performance in healthy animals. Overall, our simulations suggest that the effects of dopamine loss on synaptic plasticity play an essential role in the development of Parkinsonian symptoms, thus arguing for a re-conceptualisation of Parkinsonian pathophysiology. [ABSTRACT FROM AUTHOR]

Copyright of European Journal of Neuroscience is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)