Cav2.3 channels stimulate in vivo burst activity of vulnerable dopamine neurons and are elevated in Parkinson’s disease

The progressive degeneration of dopamine neurons (DAN) in the Substantia nigra (SN) is a hallmark of Parkinson’s disease (PD). R-type voltage gated Ca2+ channels (Cav2.3) contribute to activity-related Ca2+-influx in SN DAN which is linked to PD-pathology, and Cav2.3 knockout confers resistance to their degeneration. However, underlying mechanism, and Cav2.3 functions in DAN remain elusive. By recording immuno-identified SN DANs in vivo, we show that in Cav2.3 knockout mice burst firing - associated with elevated Ca2+-influx - is attenuated, specifically in calbindin-negative DAN in the medial SN. Overall firing rates, evoked striatal dopamine release, and related motor behaviour were not compromised. Conversely, in PD-mice (overexpressing human α-synuclein), SN DAN displayed increased burst activity, and higher Cav2.3 expression. Cav2.3 mRNA was also elevated in SN DAN from PD-patients. These findings identify R-type channels as key drivers of SN DAN burst activity and pathophysiology, and strongly suggest their therapeutic inhibition in PD. *Marta Vesnaver, Gabriel Gschwend & Linus Dentler are shared first authors.