Mechanism of Manganese Dysregulation of Dopamine Neuronal Activity
Min Lin, Luis M. Colón-Pérez, Danielle Sambo, Douglas R. Miller, Joseph J. Lebowitz, Felix R. Jimenez, Robert J. Cousins, Nicole A. Horenstein, Tolunay Beker Aydemir, Marcelo Febo, Habibeh Khoshbouei
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 in vivo studies in male C57BLJ mice suggest that manganese accumulates in dopamine neurons of the VTA and substantia nigra via nifedipine-sensitive Ca 21 channels. Manganese produces a Ca 21 channel-mediated current, which increases neurotransmitter release and rhythmic firing activity of dopamine neurons. These increases are prevented by blockade of Ca 21 channels and depend on downstream recruitment of Ca 21 -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.