Mutant α -synuclein overexpression induces stressless pacemaking in vagal motoneurons at risk in parkinson’s disease

α -Synuclein overexpression (ASOX) drives the formation of toxic aggregates in neurons vulnerable in Parkinson’s disease (PD), including dopaminergic neurons of the substantia nigra (SN) and cholinergic neurons of the dorsal motor nucleus of the vagus (DMV). Just as these populations differ in when they exhibit α -synucleinopathies during PD pathogenesis, they could also differ in their physiological responses to ASOX. An ASOX-mediated hyperactivity of SN dopamine neurons, which was caused by oxidative dysfunction of Kv4.3 potassium channels, was recently identified in transgenic (A53T-SNCA) mice overexpressing mutated human α -synuclein. Noting that DMVneurons display extensive α -synucleinopathies earlier than SN dopamine neurons while exhibiting milder cell loss in PD, we aimed to define the electrophysiological properties of DMV neurons in A53T-SNCA mice. We found that DMV neurons maintain normal firing rates in response to ASOX. Moreover, Kv4.3 channels in DMV neurons exhibit no oxidative dysfunction in the A53T-SNCA mice, which could only be recapitulated in wild-type mice by glutathione dialysis. Two-photon imaging of redox-sensitive GFP corroborated the finding that mitochondrial oxidative stress was diminished in DMV neurons in the A53T-SNCA mice. This reduction in oxidative stress resulted from a transcriptional downregulation of voltage-activated (Cav) calcium channels inDMVneurons, which led to a reduction in activity-dependent calcium influx via Cav channels. Thus, ASOX induces a homeostatic remodeling with improved redox signaling in DMVneurons, which could explain the differential vulnerability of SN dopamine andDMVneurons in PD and could promote neuroprotective strategies that emulate endogenous homeostatic responses to ASOX (e.g., stressless pacemaking) in DMV neurons.