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

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

New York

Congreso; JPB Joint Consortia Meeting; 2018

JPB

Pedunculopontine nucleus (PPN) cholinergic neurons (PPN-ChNs) play an important role in movement control and sleep, two functions that are compromised in Parkinson?s Disease (PD). Studies in PD patients have shown that near 40% of PPN-ChNs are lost, providing a potential explanation for their gait, posture and sleep symptoms. Why PPN-ChNs degenerate in PD is unclear. One possibility is that their intrinsic properties contribute to their vulnerability. Intrinsic properties ? like pacemaking and basal mitochondrial oxidant stress ? have been hypothesized to contribute to the vulnerability of substantia nigra (SN) dopaminergic (DA) neurons. The extent to which PPN-ChNs phenocopy these neurons is uncertain. To determine the degree of similarity between these two vulnerable cell types, a combination of electrophysiological and optical approaches were used to study PPN-ChNs in ex vivo brain slices from transgenic mice. PPN ChNs were slow autonomous pacemakers with broad action potentials. Pacemaking was dependent upon Cav1 calcium channels, as inhibition of these channels with dihydropyridines slowed pacemaking rate. In contrast to SNc DA neurons, pacemaking in PPN-ChNs was accompanied only by modest oscillations in cytosolic calcium concentration. Finally, basal mitochondrial oxidant stress was elevated in PPN-ChNs and this stress was 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 the JPB Foundation (DJS), NIH 50 NS047085 (DJS) and a Flanagan Fellowship (CT).