engleski

Developmental consequences of perinatally altered serotonin metabolism in rats: relationship between central and peripheral serotonin compartments

In mammals, serotonin (5HT) is present both in the brain (central 5HT compartment) and peripheral tissues (peripheral 5HT compartment) which are two separated, yet closely related entities. On one hand, 5HT is synthesized and regulated independently in the two compartments separated by the blood-brain barrier. On the other hand, proteins that regulate 5HT function in both compartments are encoded by the same genes, have identical primary structures and follow the same kinetics. Moreover, during perinatal development, the blood-brain barrier is not fully formed and serotonin can freely cross between the compartments. In the developing brain, serotonin acts as a key regulator of serotonergic outgrowth and maturation of target regions. 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 central 5HT malfunctioning are less clear. In our earlier study we showed that perinatal treatment with the immediate 5HT precursor, 5-hydroxytryptophan (5HTP), significantly raised peripheral but not central 5HT concentrations, while the perinatal treatment with the monoamine oxidase inhibitor, tranylcypromine (TCP), induced significant 5HT elevations in both compartments. The aim of this study was to compare the extent of developmental disturbances caused by perinatal alteration in peripheral 5HT homeostasis to those caused by perinatal alteration in both, peripheral and central 5HT homeostasis. Wistar rats were treated with either 25mg/kg of 5HTP or 2mg/kg TCP, from GD 13 until birth by subcutaneous injections to pregnant females, and from PND1 until PND 21 by receiving subcutaneous injections themselves. Separation anxiety was assessed through number and duration of ultrasonic separation calls (40 kHz of pups to the mother and 50 kHz of juvenile rats to conspecifics) recorded on PNDs 13, 16 and 18. Brain samples were collected on PND 22. Cytoarchitecture of barrel fields was analyzed after Nissl staining of tangentially oriented serial sections across the dorsolateral telencephalic wall. Compared to the saline- treated controls, pups from both experimental groups had decreased viability (25% were still born or died within 48 hrs) and significantly lower body mass throughout the entire postnatal period. Both treatments altered the formation of the barrel cortex. Disturbances in size and organization of the barrel fields, as well as in delineation and number of barrels in the field were more pronounced in TCP-treated animals. 5HTP treatment induced slight, non- significant increase in separation anxiety and a slight delay in switching from 40 to 50 kHz calls (PND18 vs. PND16 in controls). TCP treatment induced significant increase in separation anxiety at all three time-points with calls retaining a 40 kHz frequency. The obtained results suggest that exposure of the developing brain to increased 5HT concentrations may lead to structural and behavioral abnormalities indicative of developmental delay. Developmental disturbances induced by perinatal alteration 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.

Serotonin; hiperserotoninemija; razvoj; ultrazvučne vokalizacije; bačvasta polja

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