Synaptic Plasticity of Basal Ganglia Output Neurons in Movement Disorders

Information storage in the central nervous system is believed to emerge from changes in the functional efficacy of synaptic connections, a property known as synaptic plasticity. Parkinson's disease (PD) and dystonia are movement disorders that are the result of basal ganglia dysfunction. In PD, basal ganglia abnormalities are the result of the loss of dopamine, which leads to paucity of movements, rigidity of the limbs, and rest tremor. A unique characteristic of synaptic plasticity in the basal ganglia is that a certain level of endogenous dopamine and dopamine receptor activation seems to be required for its induction. In dystonia, a model has emerged in which a fundamental deficit within the basal ganglia generates impaired inhibition in the motor cortex that results in increased excitability, abnormal processing of sensory feedback and increased striatal, brainstem, and cortical plasticity. This thesis addresses the question of whether movement disorders such as PD and dystonia are associated with abnormal plasticity in the output nuclei of the basal ganglia, the SNr and the GPi. To do this, a pair of microelectrodes was used to simultaneously stimulate and record alterations in field evoked potentials (fEPs) from the substantia nigra pars reticulata (SNr) and the internal segment of the globus pallidus (GPi) using a variety of stimulation protocols in patients undergoing stereotactic neurosurgery for the implantation of deep brain stimulating (DBS) electrodes for treatment of PD or dystonia. Using these methods, we have previously shown that activity-dependent synaptic plasticity is measurable in the SNr of PD patients and that this plasticity is sensitive to low doses of L-dopa. Here we demonstrate for the first time, that activity-dependent synaptic plasticity is also present in human GPi. Also, we provide additional evidence that the fEP is the result of primarily striatopallidal and striatonigral activation, and show that the fEP is useful in confirming microelectrode position and even in revealing functional deafferentiation. Furthermore, we demonstrate that short interval inhibition is reduced in basal ganglia output nuclei of dystonic patients and partially normalized following high frequency stimulation (HFS). In both generalized and cervical dystonia, the paired pulse ratio at low interstimulus intervals correlates with motor dysfunction, suggesting that abnormalities exist in synaptic function of striatopallidal and / or striatonigral terminals in dystonia patients and that such abnormalities may be contributing to the pathophysiology of dystonia, either independent of, or in addition to the increased excitability and plasticity observed in cortical areas in dystonia patients. Finally, we demonstrate a lack of a form of plasticity called depotentiation in basal ganglia output nuclei of PD patients with dyskinesia. The ability of a synapse to reverse previous potentiation may be crucial to prevent saturation of the storage capacity of motor information. Loss of this ability at the output nuclei could lead to the basal ganglia retaining unessential information that is normally erased, and may underlie, or at the very least contribute to the cellular basis for dyskinetic movements. Together, these findings suggest that abnormal plasticity in the basal ganglia output nuclei plays an important role in movement disorders such as PD and dystonia and that altered long-lasting changes in synaptic transmission represent an important mechanism by which basal ganglia function is impaired in movement disorders.

Advisor: William, D Hutchison