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Investigation of the Brain Serotonin System Plasticity Using the Recombinant Mouse Lines Carring 1473G–Allele of Tryptophan Hydroxylase-2 Gene and Differing by the Distal Fragment of Chromosome 13 Containing 5-HT1A Receptor Gene

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Abstract—In order to investigate the joint influence of C1473G polymorphism in the gene encoding the key enzyme for serotonin (5-HT) biosynthesis in brain – tryptophan hydroxylase-2, and the distal fragment (103,9-112,4 Мbp) of chromosome 13, including 5-HT1A serotonin receptor gene from catalepsy-prone CBA strain, on the brain 5-HT system, new recombinant mice strain B6-1473GG.CBA-CD13Mit76С (1473GG-76C) and B6-1473GG.CBA-D13Mit76В (1473GG-76B) on the base of C57BL/6 strain were created. The 1473GG-76C and 1473GG-76B lines carry a fragment of chromosome 13 containing Htr1a gene from the CBA and the C57BL/6 strains respectively. Both lines are homozygous by 1473G-allele, reducing the activity of TPH-2. It was shown that the 1473GG-76C line is characterized by increased levels of mRNA of Htr1a, Htr2a genes and Maoa gene (monoamine oxidase type A—the main enzyme of 5-HT degradation) in the midbrain, Htr1a gene in the cortex, Htr1a and Htr2a genes in the hippocampus as compared to 1473GG-76B. In addition, the 1473GG-76C line has increased expression of genes encoding the key regulators of Htr1a gene—FREUD-1 and FREUD-2. The mRNA level of the Cc2d1a gene encoding FREUD-1 was increased in the cortex, and the expression of the Cc2d1b gene encoding FREUD-2 was enhanced in the midbrain. Also, the 1473GG-76C line has increased 5-HT levels in the midbrain, hypothalamus and hippocampus. At the same time, the level of the main 5-HT metabolite, 5-HIAA, was decreased in the midbrain and cortex of these mice. The ratio of 5-HIAA/5-HT reflecting the intensity of 5-HT metabolism was reduced in all investigated structures of 1473GG-76C mice. Thus, the combination of 1473G-allelele of Tph2 gene with Htr1a gene from the CBA strain had a significant effect on the mRNA levels of the key genes of the 5-HT system and on 5-HT metabolism in the brain of 1473GG-76C mice.

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Funding

This study was supported by the Russian Science Foundation (grant no. 19-15-00027). The maintenance of the animals was supported by the basic research project no. 0259-2019-0002-С-01.

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  1. Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, pr. Akademika Lavrent’eva, 10, 630090, Novosibirsk, Russia

    A. Ya. Rodnyy, I. I. Belokopytova, E. V. Antonov, V. S. Naumenko & E. M. Kondaurova

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  1. A. Ya. Rodnyy
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  2. I. I. Belokopytova
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  4. V. S. Naumenko
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Correspondence to A. Ya. Rodnyy.

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Statement on the welfare of animals. The experimental animals were bred and managed, and all procedures were performed in accordance with the International Guide for the Care and Use of Laboratory Animals, Eighth Edition, Committee for the Update of the Guide for the Care and Use of Laboratory Animals; National Research Council © 2011 National Academy of Sciences (United States) and national documents: Guidelines for Good Laboratory Practice in the Russian Federation adopted by the order of Ministry of Health of the Russian Federation No. 199n of April 01, 2016; GOST standards 33215-2014 “Guidelines for the Breeding, Care and Management of Laboratory Animals” (Guidelines on Laboratory Animal Facilities and Animal Procedures, adopted July 1, 2015). The conditions for breeding of animals and the experimental procedures were approved by the ethics committee of the Institute of Cytology and Genetics (Novosibirsk, Russia).

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Rodnyy, A.Y., Belokopytova, I.I., Antonov, E.V. et al. Investigation of the Brain Serotonin System Plasticity Using the Recombinant Mouse Lines Carring 1473G–Allele of Tryptophan Hydroxylase-2 Gene and Differing by the Distal Fragment of Chromosome 13 Containing 5-HT1A Receptor Gene. Neurochem. J. 14, 384–393 (2020). https://doi.org/10.1134/S1819712420040078

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