engleski

The role of hyperserotonemia in neurodevelopmental disorders: studies on rats with perinatally altered serotonin metabolism

In mammals, serotonin (5HT) is present both in the brain (central 5HT compartment) and peripheral tissues (peripheral 5HT compartment). In the developing brain, serotonin acts as a key regulator of serotonergic outgrowth and synaptogenesis. Therefore, perinatally altered 5HT homeostasis could lead to deviations from optimal 5HT concentrations, affecting so the development of the brain serotonergic system and later leading to the related behavioral deficits. Although central 5HT disturbances are strongly indicated in several neurodevelopmental disorders, the role of peripheral 5HT dysregulation, and its relationship to the central 5HT malfunctioning are less clear. In order to study the consequences of perinatal disturbances in serotonin metabolism, we exposed developing Wistar rats to treatments with the immediate 5HT precursor 5-hydroxytryptophan (5HTP, 25mg/kg), or the monoamine oxidase (MAO) inhibitor tranylcypromine (TCP, 2mg/kg) from gestational day 12 until postnatal day 21. Treatment with 5HTP significantly raised peripheral but not central 5HT concentrations, while treatment with TCP induced significant 5HT elevations in both compartments, allowing us to compare the extent of 5HT-related disturbances induced by alteration in only peripheral vs. peripheral and central 5HT homeostasis. Developmental consequences were observed in both groups of animals (compared to the saline-treated controls, pups had decreased viability, significantly lower body mass throughout the entire postnatal period, altered formation of the barrel cortex and increased separation anxiety) but were more prominent in TCP-treated rats. In 5HTP-treated rats, peripheral 5HT homeostasis was re-established while modest decrease in 5HT concentration in frontal cortex remained at adult age. In TCP-treated rats, imbalances in 5HT homeostasis remained at adult age, both peripherally (as hyperserotonemia) and centrally (as altered 5HT metabolism with markedly decreased 5HT concentrations). The obtained results indicate that exposure of developing brain to the increased 5HT concentrations may lead to structural and behavioral abnormalities indicative of developmental delay. Developmental disturbances induced by perinatal alterations in both 5HT compartments were much more pronounced than those induced by perinatal alteration only in the peripheral 5HT-compartment indicating that hyperserotonemia alone might not be sufficient to cause 5HT-related disturbances in neurodevelopmental syndromes. Still, transient fetal/neonatal (along with maternal) hyperserotonemia in 5HTP-treated animals was sufficient to induce measurable 5HT-related changes, suggesting a caution in the use of this 5HT enhancer by pregnant women. Finally, permanent alterations in the central 5HT homeostasis induced by developmental disturbances in 5HT synthesis or degradation suggest that genes which regulate 5HT metabolism might be considered as potential candidates in 5HT-related behavioral disorders.

serotonin; hyperserotonemia; neurodevelopmental disorders; 5-hydroxytryptophan; tranylcypromine

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