title: Interactions between TrkB signaling and serotonin excess in the developing murine somatosensory cortex: a role in tangential and radial organization of thalamocortical axons.
abstract: Mice lacking monoamine oxidase A (MAOA) display high levels of brain serotonin during the first postnatal week, causing an exuberant outgrowth of thalamocortical axons (TCAs) in layer IV of the somatosensory cortex (S1). We asked whether this exuberance is attributable to abnormal TrkB signaling, because modulation of TrkB signaling during a critical period dramatically influences the segregation and the morphology of TCAs in layer IV of the visual cortex. Using in situ hybridization and ELISA immunoassays, we showed that the levels of trkB mRNA and BDNF and neurotrophin-4 (NT-4) proteins are normal in the thalamus and the cortex of mice lacking MAOA during barrel field formation. Because the release of BDNF and NT-4 could be abnormal in MAOA knock-out (KO) mice, we tested whether abnormal TrkB signaling is required for TCA exuberance in MAOA-KO mice by generating mice lacking both trkB and MAOA. Surprisingly, these mice exhibited more severe phenotypes than those found in MAOA-KO mice: a widespread tangential expansion of TCAs in layer IV of the cortex, resulting in a fusion of all sensory representations and a radial expansion of TCAs in layers II-III of the cortex. Careful examination of mice lacking trkB alone revealed subtle alterations of TCAs, with abnormal invasion of layer III. This study reveals the following: (1) expression of trkB, BDNF, and NT-4 are not modulated by an excess of serotonin during barrel formation, (2) TrkB signaling limits branching of TCAs in inappropriate supragranular cortical layers, and (3) serotonin and TrkB signaling act together to cluster thalamocortical axons in layer IV.
authors.affiliation: Department of Biomedical Sciences, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom. ucgatvi@ucl.ac.uk
authors.forename: Tania
authors.initials: T
authors.lastname: Vitalis
authors.forename: Olivier
authors.initials: O
authors.lastname: Cases
authors.forename: Katy
authors.initials: K
authors.lastname: Gillies
authors.forename: Naima
authors.initials: N
authors.lastname: Hanoun
authors.forename: Michel
authors.initials: M
authors.lastname: Hamon
authors.forename: Isabelle
authors.initials: I
authors.lastname: Seif
authors.forename: Patricia
authors.initials: P
authors.lastname: Gaspar
authors.forename: Peter
authors.initials: P
authors.lastname: Kind
authors.forename: David J
authors.initials: DJ
authors.lastname: Price
mesh_terms: D000818:Animals; D001369:Axons / Q000648:ultrastructure*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D016923:Cell Death; D002540:Cerebral Cortex / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000032:analysis; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D008995:Monoamine Oxidase / Q000235:genetics; D009414:Nerve Growth Factors / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000096:biosynthesis*; D015398:Signal Transduction; D013003:Somatosensory Cortex / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D013788:Thalamus / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D008995:Monoamine Oxidase; D003576:Electron Transport Complex IV; D020813:Receptor, trkB; C073922:neurotrophin 4