Effects of prolonged exposure to manganese chloride on the brain serotonin metabolism and serotonin-regulated behavior in zebrafish

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Abstract

Manganese ions are toxic for the central nervous system and cause motor impairment. Zebrafish (Danio rerio) are widely used in neuroscience, psychopharmacology and toxicology. The study was aimed to investigate the effect of prolonged exposure to Mn ions on the serotonin (5-HT) system of the brain and the 5-HT controlled behavior in zebrafish. The studies were carried out on males and females of zebrafish line AB, which were divided into four groups: control and which were exposed to 0.1, 0.2 and 0.5 mM MnCl2 for 10 days (the drug was added to the aquarium water). Throughout the exposure, the locomotion of fish were continuously recorded and analyzed using DanioStudio software. On the 11th day of exposure, the behavior of the fish was studied in the novel tank diving test, then the levels of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), the activity of key enzymes in the synthesis and destruction of 5-HT, tryptophan hydroxylase (TPH) and monoamine oxidase (MAO), respectively, were determined in their brain by HPLC. Prolonged exposure to MnCl2 did not affect body mass, locomotor activity, time in the lower and upper thirds of the home aquarium, as well as locomotor and exploration activities, time in the lower and upper thirds in the novel tank diving test. Moreover, the prolonged exposure to MnCl2 did not affect 5-HT, 5-HIAA levels and MAO activity in fish brain. However, TPH activity was significantly increased in fish kept at 0.2 and 0.5 mM MnCl2. In an additional experiment, Mn ions were shown to increase the thermal stability of the TPH molecule in vitro. This stabilizing (chaperone) activity of Mn ions was demonstrated for the first time. The discovery of the chaperone activity of Mn ions will help to reveal the fundamental molecular principles and mechanisms of action of pharmacological chaperones.

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About the authors

А. E. Izyurov

Institute of Cytology and Genetics SD RAS

Email: avkulikov52@gmail.com
Russian Federation, Novosibirsk

I. E. Sorokin

Institute of Cytology and Genetics SD RAS

Email: avkulikov52@gmail.com
Russian Federation, Novosibirsk

V. S. Evsiukova

Institute of Cytology and Genetics SD RAS

Email: avkulikov52@gmail.com
Russian Federation, Novosibirsk

D. А. Zolotova

Institute of Cytology and Genetics SD RAS

Email: avkulikov52@gmail.com
Russian Federation, Novosibirsk

P. A. Kulikov

Institute of Cytology and Genetics SD RAS

Email: avkulikov52@gmail.com
Russian Federation, Novosibirsk

A. V. Kulikov

Institute of Cytology and Genetics SD RAS

Author for correspondence.
Email: avkulikov52@gmail.com
Russian Federation, Novosibirsk

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Supplementary files

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2. Fig. 1. Motor activity, time spent (%) in the upper and lower thirds of the home aquarium in fish maintained for 10 days in water with 0 (control), 0.1, 0.2, 0.5 mM MnCl2. Dots represent the mean values ​​of observations 12 h per day for 10 days for each aquarium. Bars represent the mean values ​​± the error of the mean for each aquarium. The number of aquariums in each group n = 4.

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3. Fig. 2. Body weight (g), distance traveled (m), proportion of the surveyed space (%), distance from the bottom (cm), time spent (%) in the upper and lower thirds of the cuvette in fish kept for 10 days in water with 0 (control), 0.1, 0.2, 0.5 mM MnCl2. Dots represent individual values. Lines represent mean values ​​± standard errors for each aquarium. Each of the 4 groups included 20 fish. **p < 0.01 vs control.

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4. Fig. 3. 5-HT level (ng/mg), 5-HIAA level (ng/mg) and 5-HIAA/5-HT ratio in the brain of fish maintained for 10 days in water with 0 (control) (n = 11), 0.1 (n = 9), 0.2 (n = 10), 0.5 (n = 10) mM MnCl2. Dots represent individual values. Bars represent mean values ​​± SEM for each aquarium.

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5. Fig. 4. MAO (pmol/mg/min) and TPG (pmol/mg/min) activities in the brain of fish maintained for 10 days in water with 0 (control) (n = 11), 0.1 (n = 9), 0.2 (n = 10), 0.5 (n = 10) mM MnCl2. Dots represent individual values. Bars represent mean values ​​± SEM for each aquarium. *p < 0.05, ***p < 0.001 vs control.

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6. Fig. 5. T50 values ​​for TPG from D. rerio brain in the absence (control) and presence of 0.05 mM MnCl2. Dots represent individual T50 values. Each group included 6 values. Bars represent mean values ​​± SEM for each aquarium. *p < 0.05 vs control.

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