Nadezhda A. Sinyakova

Tryptophan hydroxylase 2 (TPH2) hydroxylates L-tryptophan to L-5-hydroxy tryptophan—the key step of 5-HT synthesis in the mammalian brain. Some mutations in the human hTPH2 gene are associated with psychopathologies and resistance to antidepressant therapy. The C1473G polymorphism in the mouse Tph2 gene decreases the TPH2 activity in the mouse brain. In the present paper, B6-1473C and B6-1473G congenic mice that were different only in the C > G substitution were used. The molecular mechanism of decrease in the mutant enzyme activity and some physiological and behavioral traits affected by this mutation were revealed for the first time. Analysis of thermal denaturation curves in vitro revealed that the C > G substitution reduces the free energy of denaturation, stability and lifetime of mutant TPH2. Later, we evaluated the effect of the 1473G allele on the hierarchical state, competition for a sexual partner in adult mice, mouse embryos, hind legs dystonia and the response to LPS treatment in young mice. No effect of this mutation on the hierarchical state and competition for a female was observed in adult males. The C > G substitution does not affect survival, body mass or the TPH activity in the brain of 19-day-old mouse embryos. At the same time, we found that the 1473G allele causes hind legs dystonia in juvenile (3 weeks old) mice, which can affect their escape capability in threatening situations. Moreover, a significant increase in the vulnerability to LPS in juvenile B6-1473G males was shown: a single ip LPS administration killed about 40% of young mutant mice, but not wild-type ones. The body mass of mutant males was lower compared to wild-type ones, which also can indirectly decrease their concurrent and reproductive success.

A decrease in the light in autumn and winter causes depression like seasonal affective disorders (SAD) in sensitive patients, in which the serotonin (5-HT) and dopamine (DA) brain mediator systems are involved. We studied the interaction of the 5-HT and DA brain systems in an experimental SAD model in sexually mature male mice of the congenic B6-1473C and B6-1473G lines with high and low activity of tryptophan hydroxylase 2, a key enzyme of 5-HT synthesis in the brain. Mice of each line (divided into two groups of eight individuals) were kept for 30 days in standard (14 h light/10 h dark) and short (4 h light/20 h dark) daylight. The presence of the C1473G variant in the tryptophan hydroxylase 2 gene did not affect the expression of key genes of DA system: Drd1, Drd2, Scl6a3, Th, and Comt, that encode the D1 and D2 receptors, dopamine transporter, tyrosine hydroxylase, and catechol-o-methyltransferase, respectively. A decrease in the level of DA in the midbrain, as well as of its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum, was detected in B6-1473G mice. Keeping mice in short daylight did not affect expression of the Drd1 gene in all brain structures nor the expression of the Slc6a3 and Th genes in the midbrain. Drd2 expression increased in the midbrain and decreased in the hippocampus, where Comt expression increased. An increase in DA level in the midbrain and DOPAC in the striatum was detected in mice kept in short daylight. This indicates the involvement of the brain’s DA system in the reaction to a decrease in daylight duration. No statistically significant effect of the interaction between the presence of the C1473G variant and daylight length on indicators of the activity of DA system was detected. No reasons were found to assert that this polymorphism determines the observed reaction of the brain DA system in keeping of animals under short daylight conditions.

A decrease in the light in autumn and winter causes depression like seasonal affective disorders (SAD) in sensitive patients, in which the serotonin (5-HT)

We compared the effect of a new potential antidepressant 8-trifluoromethyl 1,2,3,4,5-benzopentathiepine-6-amine hydrochloride (TC-2153) and classical antidepressant fluoxetine in a dose of 0.25 mg/liter on the behavior of Danio rerio in the “novel tank” test and content of biogenic amines and their metabolites in the brain. Fluoxetine alone and TC-2153 alone significantly increased the time spent in the upper part of the tank and insignificantly reduced motor activity. Combined exposure of fishes in the solution containing potential and classical antidepressants potentiated their effects on both parameters. The compounds did not affect brain contents of serotonin, dopamine, and norepinephrine. At the same time, fluoxetine, but not TC-2153, reduced brain content of the main serotonin metabolite 5-hydroxyindole acetic acid.

Catalepsy usually is caused by imbalance of dopamine (DA) and serotonin (5-HT) systems of brain. The aim of our work was to verify if this imbalance plays an important role in the mechanism of hereditary catalepsy in mice. Maintenance of DA, 5-HT and their main metabolites--5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, homovanilic acid was determined in cortex, hypothalamus, hippocampus, striatum, substantia nigra and nuclei raphes in catalepsy-resistant AKR/J mice strain and catalepsy-prone CBA/LacJ mice strain and recombinant mice AKR/J.CBA-D13Mit76 (D13) strain. The latest strain was selected by transferring of a fragment of the chromosome 13 from CBA/LacJ carrying the main gene of hereditary catalepsy to AKR/J genome. There were no interstrain differences in concentration of biogenic amines and their metabolites in all brain regions. As a result of our work the hypothesis about the important role of 5-HT and/or DA systems of brain in the mechanism of hereditary catalepsy in mice was denied.

Catalepsy is a pathological animal behavior that is usually associated with dysfunctions in the striatal pallidal system of the brain and can be caused by different reasons. It was previously...