FUNCTIONAL AND ANATOMICAL REMODELING OF INHIBITORY PALLIDAL INPUTS TO THE SUBTHALAMIC NUCLEUS IN MPTP-TREATED PARKINSONIAN MONKEYS

The subthalamic nucleus (STN) and external globus pallidus (GPe) are reciprocally connected components of the basal ganglia indirect pathway. Altered STN firing patterns following nigrostriatal dopaminergic denervation correlate with the severity of parkinsonism. In rodents with nigrostriatal lesions, the strength of the GABAergic GPe-STN connection increases, with increased number of synapses per GPe terminal, potentially contributing to abnormalities of STN firing in parkinsonism (Fan et al., 2012). We investigated whether similar plasticity also occurs in parkinsonian monkeys. We examined the responses of STN neurons to electrical GPe stimulation in two awake monkeys using extracellular electrophysiologic recordings before and after MPTP-induced parkinsonism. GPe stimulation (bipolar, 500 μA, 100 μs/phase, 1 mm contact separation) elicited a significant modulation of STN local field potentials (LFPs) under normal conditions. After MPTP, LFP modulations were delayed and prolonged. Confocal fluorescence microscopy of STN tissue from our primate brain bank (three healthy and three parkinsonian animals) showed no significant changes in the density of GABAergic terminals in the STN. 3D electron microscopic reconstructions of 45 and 52 putative GABAergic pallidal terminals in STN tissue of two control and two parkinsonian monkeys, respectively allowed us to quantify terminal volumes, synaptic flat areas, and mitochondrial number and size. Parkinsonian monkeys showed significantly smaller average GPe terminal volumes but larger and complex postsynaptic flat areas than controls. These findings suggest that MPTP treatment induces functional and morphological changes of GPe-STN terminals in non-human primates potentially contributing to altered STN responses to GPe inputs in parkinsonism.