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

Abstract

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.