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Activity-dependent neuronal calcium signalling and its role in aging and Parkinson’s disease

13. December 2022

CTNR Lecture Series: Prof. Dr. Birgit Liss (University of Ulm)

Date: 13 December 2022, 15:30 - 17:00
Place: Hörsaal, Zentrum f. Nervenheilkunde, Gehlsheimer Str. 20, Gehlsdorf

Lecturer: Prof. Dr. Birgit Liss, University of Ulm, Department of Applied Physiology
Title: „Activity-dependent neuronal calcium signalling and its role in aging and Parkinson’s disease“

Abstract:
The progressive loss of dopaminergic (DA) neurons within the Substantia nigra (SN) is a general feature of the aging brain and causes the main motor symptoms of Parkinson’s disease (PD). The two main neuropathological hallmarks of PD are differential neuronal vulnerability, and formation of toxic α-synuclein aggregates, so-called Lewy-bodies (LB). While DA neurons within the SN exhibit the highest cell loss during PD, DA neurons in the neighboring ventral tegmental area (VTA) remain largely intact. Moreover, cholinergic neurons within the dorsal motor nucleus of the vagus (DMV), do show early LB-formation and a similar pacemaker-activity as SN DA neurons, but are less affected by PD-stressors. The cause for this differential neuronal vulnerability is still unclear. However, the intrinsic electrical activity, orchestrated by distinct ion channels, as well as activityrelated metabolic stress and calcium homeostasis are important factors. To identify mechanisms defining neuronal vulnerabilities in age and PD, we are analyzing mice overexpressing human wildtype (SNCA OVX) or mutant α-synuclein (A53T), causing familial forms of PD (PARK4, PARK1), as well as post mortem human brains from PD patients. SN DA neurons of A53T mice display elevated metabolic stress, accompanied by redox-impaired inhibitory A-type K+ channels (particularly Kv4.3), while in DMV neurons, metabolic stress levels are even lower,compared to those of wildtype (WT). Here, we focus on voltage gated Ca2+ channels (Cav) and Ca2+ and voltage gated A-type channels. We quantify mRNA and proteins of Cav and Kv4 channel α and β subunits in mouse and human DA and DMV neurons via RNAscope in situ hybridization and immunohistochemistry, combined with automated, artificial intelligence based cell-recognition and signal-quantification (Wolution). We also compare electrophysiological (Patch clamp, MEA) and mitochondrial respiration properties (Seahorse) of highly vulnerable and resistant neurons in vital mouse brain slices. Our results that will be presented in this tal, support the hypothesis that neurons that alter their electrical activity and reduce intrinsic metabolic stress, e.g. via adaptive Cav channel signalling, are less vulnerable in PD-paradigms.

Host: Prof. Rüdiger Köhling (Oscar-Langendorff-Institute of Physiology), Prof. Georg Fuellen (Institute for Biostatistics and Informatics)

Registration for Dinner (only for IPHY/IBIMA staff, 17 - 21:00, Casino Gehlsdorf)