Blockade of nifedipine‐sensitive Ca2+ channels decreases manganese accumulation on the dopamine neurons

Abstract

Manganese (Mn) is an essential trace element involved in many physiological processes. Mn is transported into the cells through a number of transporters. Overexposure to Mn leads to its accumulation in the basal ganglia where it induces circuit dysregulation and a Parkinson-like syndrome referred to as manganism. The mechanisms by which Mn regulates the intrinsic firing behaviors of dopamine neurons and how Mn overexposure dysregulates this activity are not well understood. In this study, we investigated Mn's modulation of the excitability, intrinsic firing activity, Ca2+ homeostasis, and voltage-gated Ca2 channel expression in mouse dopamine neurons. We found that Mn increases the spontaneous firing activity of dopamine neuron via a concentration-dependent mechanism (10–100mM). Analysis of action potential morphology revealed that Mn truncated the amplitude and narrowed the width of action potentials and reduced coefficients of variation of the interspike interval. Unexpectedly, we found neither removal of external Ca2+ (Ca2+-free), chelation of intracellular Ca2+, nor combined chelation of internal and external Ca2+ altered Mn-regulation of action potential in dopamine neurons. Therefore, we asked whether Mn alters Ca2+ currents via the voltage-gated Ca2+ channels in the dopamine neurons. We found that Mn suppressed the peak amplitude of Ca2+ channel-mediated currents, and blockade of Ca2+ channels prevented Mn-stimulation of firing rate, reduction of action potential amplitude in dopamine neurons, and reduced 54Mn uptake in the CaV1-2, CaV1-3 expressing cells (p< 0.05, n=8–10). Finally, in vivo magnetic resonance imaging (MEMRI) revealed nifidepine-blockade of Ca2+ channels decreased Mn accumulation in the midbrain region of C57BL mice (p<0.05, n=6–8). Our data suggest a potential mechanism by which Mn can induce defects in basal ganglia function, namely a marked increase the excitability of dopaminergic neurons. Mn increases the spontaneous firing activity of dopamine neurons. Blockade of L-type Ca2+ channels inhibited Mn-stimulation of spontaneous firing activity of dopamine neurons. Manganese enhanced magnetic resonance imaging (MEMRI) provides evidence of an in vivo calcium-dependent mechanism involved in midbrain Mn accumulation. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.