Journal Article

Lack of brain serotonin affects postnatal development and serotonergic neuronal circuitry formation

Pasqualetti, M, Pacini, G, Pelosi, B, Lunardi, G, Migliarini, S

2013

Overview

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 knock-in 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 Tph2∷eGFP 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/2571 / 631/378/340 / 692/699/375/366 / Animals / Behavioral Sciences / Biological and medical sciences / Biological Psychology / Body Size / Brain / Brain - pathology / Brain Chemistry / Brain-derived neurotrophic factor / Brain-Derived Neurotrophic Factor - biosynthesis / Brain-Derived Neurotrophic Factor - genetics / Cell migration / Central nervous system / Developmental biology / Gene Knock-In Techniques / Genes / Genes, Reporter / Green Fluorescent Proteins - genetics / Growth Disorders - genetics / Growth Disorders - pathology / Growth Disorders - physiopathology / Growth rate / Hippocampus / Homeostasis / Immunoreactivity / Innervation / Lethality / Longevity / Medical sciences / Medicine / Medicine & Public Health / Mental disorders / Mice / Mice, Inbred C57BL / Morphology / Nervous system / Neural circuitry / Neural Pathways - pathology / Neurites - ultrastructure / Neurodevelopmental disorders / Neurogenesis / Neurogenesis - genetics / Neurogenesis - physiology / Neurosciences / Nucleus accumbens / original-article / Paraventricular nucleus / Pharmacotherapy / Phenotype / Physiological aspects / Physiology / Psychiatry / Psychology. Psychoanalysis. Psychiatry / Psychopathology. Psychiatry / Serotonergic Neurons - pathology / Serotonin / Serotonin - analysis / Serotonin - biosynthesis / Serotonin - deficiency / Serotonin - physiology / Thalamus / Transgenes / Tryptophan / Tryptophan hydroxylase / Tryptophan Hydroxylase - deficiency / Tryptophan Hydroxylase - genetics / Tryptophan Hydroxylase - physiology