Intrinsic properties of pedunculopontine cholinergic neurons may contribute to their vulnerability in Parkinson?s Disease.

CECILIA TUBERT; GALTIERI, DANIEL; GUZMAN, JAIME N; SURMEIER, DALTON JAMES

Berlin

Congreso; 11th FENS Forum of Neuroscience; 2018

FENS

The pedunculopontine nucleus (PPN) cholinergic neurons (PPN-ChNs) play an important role in movement control and sleep. The degeneration of these neurons in Parkinson?s disease (PD) patients could contribute to the gait and sleep deficits these patients experience. Why PPN-ChNs degenerate in PD is unclear. One possibility is that their intrinsic properties contribute to their vulnerability. For example, substantia nigra dopaminergic neurons, which die in PD, are slow autonomous pacemakers with large cytosolic calcium oscillations and high basal mitochondrial oxidant stress. These properties are hypothesized to be major drivers of their degeneration in PD. The extent to which PPN-ChNs phenocopy these neurons is uncertain. To answer this question, a combination of electrophysiological and optical approaches were used to study PPN-ChNs in ex vivo brain slices from transgenic mice. These studies revealed four key features of these neurons. First, PPN ChNs are slow (~6 Hz) autonomous pacemakers with broad action potentials. Second, their pacemaking was dependent upon Cav1 calcium channels, as inhibition of these channels with dihydropyridines slowed pacemaking rate. Third, pacemaking was accompanied by very modest (~40 nM) oscillations in cytosolic calcium concentration, contrasting them with dopaminergic neurons. Fourth, basal mitochondrial oxidant stress in PPN-ChNs was elevated and diminished by Cav1 channels inhibition. Thus, although there are similarities between PPN-ChNs and vulnerable dopaminergic neurons, there are significant differences, particularly in the extent to which Cav1 channels are engaged and their role in pacemaking.This work was supported by NIH 50 NS047085 (DJS), the JPB Foundation (DJS) and a Flanagan Fellowship (CT).