TY - JOUR T1 - Mechanism of Manganese Dysregulation of Dopamine Neuronal Activity JF - The Journal of Neuroscience JO - J. Neurosci. SP - 5871 LP - 5891 DO - 10.1523/JNEUROSCI.2830-19.2020 VL - 40 IS - 30 AU - Min Lin AU - Luis M. Colon-Perez AU - Danielle O. Sambo AU - Douglas R. Miller AU - Joseph J. Lebowitz AU - Felix Jimenez-Rondan AU - Robert J. Cousins AU - Nicole Horenstein AU - Tolunay Beker Aydemir AU - Marcelo Febo AU - Habibeh Khoshbouei Y1 - 2020/07/22 UR - http://www.jneurosci.org/content/40/30/5871.abstract N2 - 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 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.SIGNIFICANCE STATEMENT 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 in vivo. Our data provide a potential mechanism for manganese regulation of dopaminergic neurons. ER -