Mechanism of manganese dysregulation of dopamine neuronal activity

Lin, M.; Colon-Perez, L. M.; Sambo, D. O.; Miller, D. R.; Lebowitz, J. J.; Jimenez-Rondan, F.; Cousins, R. J.; Horenstein, N.; Aydemir, T. B.; Febo, M.; Khoshbouei, H.

doi:10.1101/792143

bioRxiv · 10.1101/792143

Mechanism of manganese dysregulation of dopamine neuronal activity

Lin, M.·Colon-Perez, L. M.·Sambo, D. O.·Miller, D. R.·Lebowitz, J. J.·Jimenez-Rondan, F.·Cousins, R. J.·Horenstein, N.·Aydemir, T. B.·Febo, M.·Khoshbouei, H.

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Abstract

Manganese exposure produces Parkinsons-like neurological 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 suggest manganese accumulates in dopamine neurons of the ventral tegmental area 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.\n\nSignificance StatementManganese is a trace element critical to many physiological processes. Overexposure to manganese is an environmental risk factor for neurological disorders such as a Parkinsons disease-like syndrome known as manganism. We found manganese dose-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.

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Lin, M., Colon-Perez, L. M., Sambo, D. O., Miller, D. R., Lebowitz, J. J., Jimenez-Rondan, F., Cousins, R. J., Horenstein, N., Aydemir, T. B., Febo, M., Khoshbouei, H.. 2019-10-03. Mechanism of manganese dysregulation of dopamine neuronal activity. https://doi.org/10.1101/792143

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