Effects of the Combination of the <i>C1473G</i> Mutation in the <i>Tph2</i> Gene and <i>Lethal Yellow</i> Mutations in the <i>Raly-Agouti</i> Locus on Behavior, Brain 5-HT and Melanocortin Systems in Mice
2023
Polyna D. Komleva | Ghofran Alhalabi | Arseniy E. Izyurov | Nikita V. Khotskin | Alexander V. Kulikov
Tryptophan hydroxylase 2 (TPH2) is the key and rate-limited enzyme of serotonin (5-HT) synthesis in the brain. The <i>C1473G</i> mutation in the <i>Tph2</i> gene results in a two-fold decrease in enzyme activity in the mouse brain. The <i>lethal yellow</i> (<i>A<sup>Y</sup></i>) mutation in the <i>Raly-Agouti</i> locus results in the overexpression of the <i>Agouti</i> gene in the brain and causes obesity and depressive-like behavior in mice. Herein, the possible influences of these mutations and their combination on body mass, behavior, brain 5-HT and melanocortin systems in mice of the B6-1473CC/aa. B6-1473CC/<i>A<sup>Y</sup>a</i>, B6-1473GG/aa are investigated. B6-1473GG/<i>A<sup>Y</sup>a</i> genotypes were studied. The <i>1473G</i> and <i>A<sup>Y</sup></i> alleles increase the activity of TPH2 and the expression of the <i>Agouti</i> gene, respectively, but they do not alter 5-HT and 5-HIAA levels or the expression of the genes <i>Tph2</i>, <i>Maoa</i>, <i>Slc6a4</i>, <i>Htr1a</i>, <i>Htr2a</i>, <i>Mc3r</i> and <i>Mc4r</i> in the brain. The <i>1473G</i> allele attenuates weight gain and depressive-like immobility in the forced swim test, while the <i>A<sup>Y</sup></i> allele increases body weight gain and depressive-like immobility. The combination of these alleles results in hind limb dystonia in the B6-1473GG/<i>A<sup>Y</sup>a</i> mice. This is the first evidence for the interaction between the <i>C1473G</i> and <i>A<sup>Y</sup></i> mutations.
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