Mechanism of Manganese Dysregulation of Dopamine Neuronal Activity

Abstract

Manganese exposure produces Parkinson's-like neurologic symptoms, suggesting a selective dysregulation of dopamine transmission. It is unknown, however, how manganese accumulates in dopaminergic brain regions or how it regulates the activity of dopamine neurons. Our <i>in vivo</i> studies in male C57BLJ mice suggest that manganese accumulates in dopamine neurons of the VTA and substantia nigra via nifedipine-sensitive Ca²⁺ channels. Manganese produces a Ca²⁺ channel-mediated current, which increases neurotransmitter release and rhythmic firing activity of dopamine neurons. These increases are prevented by blockade of Ca²⁺ channels and depend on downstream recruitment of Ca²⁺-activated potassium channels to the plasma membrane. These findings demonstrate the mechanism of manganese-induced dysfunction of dopamine neurons, and reveal a potential therapeutic target to attenuate manganese-induced impairment of dopamine transmission.<b>SIGNIFICANCE STATEMENT</b> Manganese is a trace element critical to many physiological processes. Overexposure to manganese is an environmental risk factor for neurologic disorders, such as a Parkinson's disease-like syndrome known as manganism. We found that manganese concentration-dependently increased the excitability of dopamine neurons, decreased the amplitude of action potentials, and narrowed action potential width. Blockade of Ca²⁺ channels prevented these effects as well as manganese accumulation in the mouse midbrain <i>in vivo</i> Our data provide a potential mechanism for manganese regulation of dopaminergic neurons.