Reelin controls the positioning of brainstem serotonergic raphe neurons

• Published in: PloS one 2018-07, Vol.13 (7), p.e0200268-e0200268
• Main Authors: Shehabeldin, Reham, Lutz, David, Karsak, Meliha, Frotscher, Michael, Krieglstein, Kerstin, Sharaf, Ahmed
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Autism; Biology; Biology and Life Sciences; Blotting, Western; Brain; Brain research; Brain stem; Brain Stem - anatomy & histology; Brain Stem - enzymology; Brain Stem - physiology; Cell Adhesion Molecules, Neuronal - physiology; Critical period; Disorders; Embryogenesis; Embryology; Embryonic development; Embryonic growth stage; Extracellular Matrix Proteins - physiology; Hindbrain; Kinases; Low density lipoprotein receptors; Medicine and Health Sciences; Mental disorders; Mice; Mice, Knockout; Nerve Tissue Proteins - physiology; Nervous system diseases; Neurobiology; Neurodevelopmental disorders; Neurological diseases; Neuromodulation; Neuronal Plasticity - physiology; Neurons; Neurophysiology; Neurosciences; Nuclei; Pathogenesis; Raphe nuclei; Raphe Nuclei - anatomy & histology; Raphe Nuclei - embryology; Raphe Nuclei - physiology; Reelin protein; Research and Analysis Methods; Rodents; Schizophrenia; Serine Endopeptidases - physiology; Serotonergic Neurons - physiology; Serotonin; Serotonin - physiology; Signal transduction; Signal Transduction - physiology; Signaling; Topography
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0200268

Serotonin (5-HT) acts as both a morphogenetic factor during early embryonic development and a neuromodulator of circuit plasticity in the mature brain. Dysregulation of serotonin signaling during critical periods is involved in developmental neurological disorders, such as schizophrenia and autism. In this study we focused on the consequences of defect reelin signaling for the development of the brainstem serotonergic raphe system. We observed that reelin signaling components are expressed by serotonergic neurons during the critical period of their lateral migration. Further, we found that reelin signaling is important for the normal migration of rostral, but not caudal hindbrain raphe nuclei and that reelin deficiency results in the malformation of the paramedian raphe nucleus and the lateral wings of the dorsal raphe nuclei. Additionally, we showed that serotonergic neurons projections to laminated brain structures were severely altered. With this study, we propose that the perturbation of canonical reelin signaling interferes with the orientation of tangentially, but not radially, migrating brainstem 5-HT neurons. Our results open the window for further studies on the interaction of reelin and serotonin and the pathogenesis of neurodevelopmental disorders.