The impact of manganese on neurotransmitter systems

Abstract

Background: Manganese (Mn) is a metal ubiquitously present in nature and essential for many living organisms. As a trace element, it is required in small amounts for the proper functioning of several important enzymes, and reports of Mn deficiency are indeed rare.

Methods: This mini-review will cover aspects of Mn toxicokinetics and its impact on brain neurotransmission, as well as its Janus-faced effects on humans and other animal's health.

Results: The estimated safe upper limit of intracellular Mn for physiological function is in anarrow range of 20-53 μM.Therefore, intake of higher levels of Mn and the outcomes, especially to the nervous system, have been well documented.

Conclusion: The metal affects mostly the brain by accumulating in specific areas, altering cognitive functions and locomotion, thus severely impacting the health of the exposed organisms.

Keywords: Manganese; Manganism; Neurotoxicity; Trace elements.

Figure 1.. Summary of the main biological effects of Mn at recommended vs elevated levels:

Mn2+-alteration of Glu transporters (EAAT), especially GLAST and GLT1 [122], impairs glutamate uptake by astrocytes resulting in an increase in extracellular glutamate concentrations [95]. The net glutamine uptake is also inhibited due to down-regulation of of SNAT1, SNAT2, and SNAT3 expression in astrocytes [90, 96]. The overall effect of manganese on GABAergic synapses is characterized by increased extracellular GABA (GABAEC) levels that is expected to be mediated through inhibition of GAT1 [103]. However, inhibition of astrocytic GAT3 was not supported by the laboratory data [110]. AMPAR - α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; EAAT - Excitatory amino acid transporter; GABA - Gamma-aminobutyric acid; GABA-T - GABA-transaminase; GAD - Glutamate decarboxylase; GAT - GABA transporter; GLAST1 - Glutamate aspartate transporter 1; GLT1 - Glutamate transporter 1; GluR - Glutamate receptor; GOT - Glutamate:oxaloacetate transaminase; NMDAR - N-methyl-D-aspartate receptor; SNAT - Sodium-coupled neutral amino acid transporter; SSADH - Succinic semialdehyde dehydrogenase; VGLUT - Vesicular glutamate transporter

Figure 2.. General effects of Mn2+ exposure in dopaminergic neurons.

The net effects of Mn exposure in dopaminergic neurons are characterized by reduced dopamine levels resulting from various mechanisms [2]. Particularly, dopamine transporters, VMAT2 and DAT, are significantly down-regulated by manganese exposure leading to impaired dopamine handling in dopaminergic synapse [123]. In addition, decreased DAT activity may also occur due to DAT internalization [124]. Manganese exposure also results in increased dopamine oxidation involving Fenton chemistry, also resulting in reduced dopamine availability [125]. Recent findings also demonstrate that Mn2+ may reduce activity of tyrosine hydroxylase, a rate-limiting enzyme of dopamine synthesis [126], although the effect is shown to be dose-, time- [127], and age-dependent [6]. These data corroborate the observation of a significant reduction in tyrosine hydroxylasepositive neurons in substantia nigra pars compacta in response to manganese treatment [128]. In addition to modulation of dopamine levels, manganese exposure was also shown to modulate dopamine receptor expression and function [129]. 3-MT - 3-Methoxytyramine; COMT - Catechol-O-methyltransferase; D1/2R - Dopamine receptor ½; DAT2 - Dopamine transporter; DOPA - 3,4-Dihydroxy-L-phenylalanine; DOPAC - 3,4-Dihydroxyphenylacetic acid; MAO - Monoamine oxidase; VMAT2 Vesicular monoamine transporter 2