α-Synuclein pathology differentially alters T-type calcium currents in vulnerable and resilient substantia nigra...

Aggregation of α-synuclein protein is a characteristic of Parkinson's disease pathology that relates to the degeneration of vulnerable dopaminergic neurons and motor symptoms of the disease. However, α-synuclein pathology can contribute to neuronal dysfunction by disrupting several processes within the cell, including intracellular calcium balance, mitochondrial function, and synaptic function. Here, we use a preformed fibril (PFF) model of synucleinopathy to examine effects of striatal α-synuclein seeding on dopamine neurons of the substantia nigra pars compacta (SNc). The SNc is heterogeneous and contains dopaminergic neurons with differential vulnerability to Parkinson's disease pathology. We found that intrastriatal injections of PFFs differentially affect these SNc neuron subtypes by increasing the excitability of resilient SNc neurons, while altering tonic firing patterns and T-type calcium currents in vulnerable SNc neurons. In addition, we performed comprehensive electrophysiological analyses and neural morphology reconstructions on SNc neurons from PFF and monomer injected mice. These findings provide insights to the selective vulnerability of SNc neuron subtypes and further our understanding of the role of α-synuclein in Parkinson's disease progression and circuit dysfunction.