Excess of serotonin affects embryonic interneuron migration through activation of the serotonin receptor 6 (original) (raw)
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The Journal of Comparative Neurology, 2004
Tissue receptor autoradiography with 3 H-lysergic acid diethylamide ( 3 H-LSD), 3 H-8hydroxy-2-[di-N-propylamine] tetralin ( 3 H-8-OH-DPAT), and 125 I-RTI-55 was used to map the distribution and developmental profile of 5-HT 1A-1D and 5-HT 2 receptors, 5-HT 1A receptors, and the serotonin (5-HT) transporter (SERT), respectively, to nuclei with cardiorespiratory function in the human medulla from midgestation to maturity. The distribution pattern of the 5-HT markers was heterogeneous, with variable densities of binding of each observed both in nuclei with and without 5-HT cell bodies. The highest density of binding for each marker was observed in the raphé nuclei, the site of the highest density of 5-HT cell bodies. A significant reduction in 5-HT receptor binding measured with 3 H-LSD was observed between midgestation and infancy, and between infancy and maturity in multiple nuclei, but no changes were observed across infancy. A significant increase in 5-HT 1A receptor binding density was observed across infancy in the hypoglossal nucleus (regression slope coefficient ϭ 0.008 Ϯ 0.002, P ϭ 0.02), and a marginally significant increase was observed in the raphé obscurus (regression slope coefficient ϭ 0.061 Ϯ 0.026 [mean Ϯ SEM], P ϭ 0.05). No significant age-related changes in SERT binding were observed at any time. With the exception of the hypoglossal nucleus, where 5-HT 1A receptor binding increases while SERT binding remains stable, the medullary 5-HT markers analyzed in the study are essentially "in place" at birth. This study provides important baseline data that serve as a foundation for future work in pediatric 5-HT brainstem disorders, including sudden infant death syndrome.
Naunyn-Schmiedeberg's Archives of Pharmacology, 1998
We have determined the pharmacological characteristics of the rat 5-ht 6 receptor stably expressed in CHO cells. Moreover, using RT-PCR experiments the in vivo expression of the gene encoding this receptor was studied in rat at various embryonic days (ED) starting from ED 10 to birth (PN 0 ) and at post-natal days (PN) up to PN 36 . The pharmacological analysis of the [ 3 H]5-HT binding in stably transfected CHO cells expressing rat 5-ht 6 receptors revealed the presence of a single class of high affinity saturable binding sites for 5-HT corresponding to an affinity constant: Kd = 27.2±3.4 nM. This receptor also exhibited a high affinity for a number of typical and atypical antipsychotics, tricyclic antidepressant drugs and ergot alkaloïds. In stably transfected CHO cells, serotonin elicited a potent stimulation of adenylyl cyclase activity which was blocked by antipsychotic and antidepressant drugs. These results confirm the hypothesis that 5-ht 6 receptors may correspond to an important target for atypical antipsychotics and reveal an original pharmacological profile for this receptor. The study of the ontogeny of the 5-ht 6 mRNA in rat developing brain showed that 5-ht 6 mRNA were first detectable with a high level on ED 12 , slighly decreased up to ED 17 and then remained stable at high level until the adult age. The ontogenetic pattern of 5-ht 6 mRNA expression appeared to correlate with the occurence of the first cell bodies of serotonergic neurons; the early expression of 5-ht 6 mRNA and the fact that this receptor is positively coupled to the production of cAMP may suggest a role for 5-ht 6 receptor in the early growth process involving the serotonergic system.
Lack of brain serotonin affects postnatal development and serotonergic neuronal circuitry formation
Molecular Psychiatry, 2012
Despite increasing evidence suggests that serotonin (5-HT) can influence neurogenesis, neuronal migration and circuitry formation, the precise role of 5-HT on central nervous system (CNS) development is only beginning to be elucidated. Moreover, how changes in serotonin homeostasis during critical developmental periods may have etiological relevance to human mental disorders, remains an unsolved question. In this study we address the consequences of 5-HT synthesis abrogation on CNS development using a knockin mouse line in which the tryptophan hydroxylase 2 (Tph2) gene is replaced by the eGFP reporter. We report that lack of brain 5-HT results in a dramatic reduction of body growth rate and in 60% lethality within the first 3 weeks after birth, with no gross anatomical changes in the brain. Thanks to the specific expression of the eGFP, we could highlight the serotonergic system independently of 5-HT immunoreactivity. We found that lack of central serotonin produces severe abnormalities in the serotonergic circuitry formation with a brain region-and time-specific effect. Indeed, we observed a striking reduction of serotonergic innervation to the suprachiasmatic and thalamic paraventricular nuclei, while a marked serotonergic hyperinnervation was found in the nucleus accumbens and hippocampus of Tph2HeGFP mutants. Finally, we demonstrated that BDNF expression is significantly up-regulated in the hippocampus of mice lacking brain 5-HT, mirroring the timing of the appearance of hyperinnervation and thus unmasking a possible regulatory feedback mechanism tuning the serotonergic neuronal circuitry formation. On the whole, these findings reveal that alterations of serotonin levels during CNS development affect the proper wiring of the brain that may produce long-lasting changes leading to neurodevelopmental disorders.
Ontogeny of 5-HT1A receptor expression in the developing hippocampus
Developmental Brain Research, 2005
Serotonin (5-HT) has long been implicated in a number of neurodevelopmental processes including neuronal cell division, migration, neurite outgrowth, and synapse formation. However, relatively little is known about how these effects are mediated during normal brain development in vivo and the identity of the receptor subtypes involved in mediating these effects. In recent years, a number of pharmacological studies have suggested a role for the serotonin 1A (5HT 1A ) receptor subtype in mediating the developmental effects of 5-HT in the hippocampus. These studies, however, have been difficult to interpret due to lack of information regarding the expression and distribution of 5HT 1A in the developing brain and hippocampus in particular. In the current study, specific anti-5-HT 1A antibodies, developed in our laboratory [Production and characterization of an anti-serotonin 1A receptor antibody which detects functional 5-HT 1A binding sites, Brain Res Mol Brain Res, 69 (1999) 186 -201], were utilized to map the ontogeny and distribution of the 5HT 1A receptor protein in the developing rat hippocampus through embryonic and early postnatal life. This is the first such study of 5-HT 1A expression in the developing rat brain. Our findings revealed that expression of the 5HT 1A receptor emerges during the initial stages of embryonic hippocampal development. Remarkably, most if not all hippocampal neurons begin to express 5HT 1A shortly upon completion of their terminal mitosis. We found that 5HT 1A is initially concentrated around the cell bodies and later becomes more sparsely distributed along the dendrites after the neurons have matured. In addition to postmitotic neurons, we have observed that S100 and GFAP positive glia transiently express 5HT 1A during early postnatal development of the hippocampus. These findings demonstrate that the 5-HT 1A receptor is positioned to mediate developmental effects of serotonin in the hippocampus. Furthermore, the temporal patterns of expression suggest a role for 5-HT 1A in postmitotic events such as neuronal migration, neurite outgrowth, and phenotypic differentiation. D 2005 Elsevier B.V. All rights reserved.
Preferential Expression of 5-HT1D over 5-HT1B Receptors during Murine Embryonic Development
Annals of the New York Academy of Sciences, 1998
THE cloning and pharmacological characterization of mouse 5-HT 1D receptors as well as the comparative analysis of its embryonic expression vs that of 5-HT 1B receptors are reported. High densities of both 5-HT 1D receptors mRNA and specific 5-HT 1D binding sites were detected at 8, 9.5, 10.5 and 13.5 days of prenatal development. In contrast, no specific 5-HT 1B binding sites could be detected until 13.5 days of development, when they were present at lower levels than 5-HT 1D receptors. This differs markedly from the situation in the adult brain, in which 5-HT 1B receptors are present at a much higher density than the 5-HT 1D subtype. These data suggest the involvement of 5-HT 1D receptors in the mitogenic and proliferative effects of serotonin during early embryonic development.
Ontogeny and regulation of the serotonin transporter: Providing insights into human disorders
Pharmacology & Therapeutics, 2011
Serotonin (5-hydroxytryptamine, 5-HT) was one of the first neurotransmitters for which a role in development was identified. Pharmacological and gene knockout studies have revealed a critical role for 5-HT in numerous processes, including cell division, neuronal migration, differentiation and synaptogenesis. An excess in brain 5-HT appears to be mechanistically linked to abnormal brain development, which in turn is associated with neurological disorders. Ambient levels of 5-HT are controlled by a vast orchestra of proteins, including a multiplicity of pre-and post-synaptic 5-HT receptors, heteroreceptors, enzymes and transporters. The 5-HT transporter (SERT, 5-HTT) is arguably the most powerful regulator of ambient extracellular 5-HT. SERT is the high-affinity uptake mechanism for 5-HT and exerts tight control over the strength and duration of serotonergic neurotransmission. Perturbation of its expression level or function has been implicated in many diseases, prominent among them are psychiatric disorders. This review synthesizes existing information on the ontogeny of SERT during embryonic and early postnatal development though adolescence, along with factors that influence its expression and function during these critical developmental windows. We integrate this knowledge to emphasize how inappropriate SERT expression or its dysregulation may be linked to the pathophysiology of psychiatric, cardiovascular and gastrointestinal diseases.
Expression of 5HT-related genes after perinatal treatment with 5HT agonists
Serotonin (5HT) is a biologically active amine with diverse roles in the mammalian organism. Developmental alterations in 5HT homeostasis could lead to exposure of the developing brain to non-optimal serotonin concentrations that may result in developmental and behavioral deficits. In order to explore the molecular basis of the effects of developmental disturbances on 5HT metabolism on adult central 5HT homeostasis, observed in our previous studies, we measured changes in gene expression of the neuronal 5HT-regulating proteins in adult animals after perinatal treatment with the immediate 5HT precursor 5-hydroxytryptophan (5HTP, 25 mg/kg), or monoamine oxidase (MAO) inhibitor tranylcypromine (TCP 2 mg/kg), during the period of the most intensive development of 5HT neurons -from gestational day 12 until postnatal day 21. Adult animals were sacrificed and the relative mRNA levels for tryptophan hydroxylase 2, MAO A, MAO B, receptors 5HT 1A and 5HT 2A , 5HT transporter (5HTT) and vesicular monoamine transporter (VMAT) were determined in the raphe nuclei region and prefrontal cortex using Real-Time Relative qRT-PCR. In comparison to the saline treated animals, treatment with 5HTP caused mild but significant increase in MAO A and MAO B mRNA abundance. TCP-treated animals, besides an increase in mRNA abundance for both MAO genes, displayed significantly increased 5HTT and VMAT2 mRNA levels and significantly decreased 5HT 1A receptor mRNA levels. Our results suggest that perinatal exposure of rats to 5HTP, and especially TCP, induces long-lasting/permanent changes in the expression of 5HT-regulating genes, that presumably underlie 5HT-related neurochemical and behavioral changes in adult animals.
Expression of 5-HT7 receptor mRNA in rat brain during postnatal development
Neuroscience Letters, 1997
The present study is the first one to demonstrate the expression of 5-HT 7 receptor mRNA by in situ hybridization during postnatal development. No quantitative developmental changes in the 5-HT 7 gene expression was observed in neocortex, pyramidal layers of CA1 and CA2, dentate gyrus, most of thalamic nuclei, mammillary region, superior colliculus and central gray. However, in retrosplenial cortex, subiculum and medial habenula an increase of labeling is observed between postnatal days (PN) PN15 and PN21. Striatum showed a transient expression during the first stages of development to be undetectable in adults. CA3 pyramidal cell layer, intramediodorsal thalamic nucleus and lateral habenula displayed a high mRNA expression at PN5 and PN8 which decreased throughout development but it was still present in adults. A possible non-neurotransmitter throphic function of 5-HT mediated through 5-HT 7 receptors could be suggested.