Inhibition of striatal dopamine release by the L-type calcium channel inhibitor isradipine co-varies with risk factors for Parkinson's

ABSTRACT

Ca2+ entry into nigrostriatal dopamine (DA) neurons and axons via L-type voltage-gated Ca2+ channels (LTCCs) contributes respectively to pacemaker activity and DA release, and has long been thought to contribute to vulnerability to degeneration in Parkinson’s disease. LTCC function is greater in DA axons and neurons from substantia nigra pars compacta than from ventral tegmental area, but this is not explained by channel expression level. We tested the hypothesis that LTCC-control of DA release is governed rather by local mechanisms, focussing on candidate biological factors known to operate differently between types of DA neurons and/or be associated with their differing vulnerability to parkinsonism, including biological sex, α-synuclein, DA transporters (DATs), and calbindin-D28k (Calb1). We detected evoked DA release ex vivo in mouse striatal slices using fast-scan cyclic voltammetry, and assessed LTCC support of DA release by detecting the inhibition of DA release by the LTCC inhibitors isradipine or CP8. Using genetic knockouts or pharmacological manipulations we identified that striatal LTCC support of DA release depended on multiple intersecting factors, in a regionally and sexually divergent manner. LTCC function was promoted by factors associated with Parkinsonian risk, including male sex, α-synuclein, DAT, and a dorsolateral co-ordinate, but limited by factors associated with protection i.e. female sex, glucocerebrosidase activity, Calb1, and ventromedial co-ordinate. Together, these data show that LTCC function in DA axons, and isradipine effect, are locally governed and suggest they vary in a manner that in turn might impact on, or reflect, the cellular stress that leads to parkinsonian degeneration.

FILE DESCRIPTIONS

This repository contains the following files:

Key Resources Table (.xlsx) - Table containing details on key lab materials (antibodies, mouse lines, and software), and the persistent identifiers for protocols and code used and generated in this study. 

Source Data (.xlsx) - Excel spreadsheet containing all tabular datasets plotted in Main Figures 1 to 5 (.xlsx).

R_Scritps (.R) - Custom written R scripts to perform a classification tree analysis.