title: Effects of genetic depletion of monoamines on somatosensory cortical development.
abstract: Raised levels of serotonin cause alterations in the development of the barrelfield of the primary somatosensory cortex (S1) in rodents. We examined the development of S1 in genetic mouse models in which the levels of serotonin and/or dopamine and noradrenaline are drastically reduced. Mice lacking the vesicular monoamine transporter type 2 (VMAT2 KO) are hypomorphic with rare pups surviving until postnatal day (P) 6. Serotonin, dopamine and noradrenaline are almost undetectable in the brain. In S1 we find that the segregation of thalamocortical axons into whisker patterns is delayed by 1 day and that layer IV granular neurons fail to form normal barrels. Moreover, the growth of cortical layers II-IV is reduced. Despite severe malnutrition, we show that these alterations are not caused by increased cell death in the thalamus or S1. Moreover, the maturation of cortical neurons is not altered as reflected by calcium-binding protein immunolabeling. Mice lacking both VMAT2 and monoamine oxidase type A (MAOA) were generated. VMAT2-MAOA DKO mice are hypomorphic but survive until P13. Increased levels of serotonin but profoundly reduced dopamine and noradrenaline levels are found in the brains. In S1, alterations are similar to those observed in MAOA KO mice: thalamocortical axons and granular neurons failed to form barrels. In addition there is a severe reduction in the thickness of the upper cortical layers as in the VMAT2 KO mice. These results show that monoamines have no instructive effect per se on the formation of thalamocortical patterning in S1. However, monoamines appear to be essential for the normal cytoarchitectonic maturation of the granular (IV) and supragranular cortical layers (II-III). Since developmental cell death and chemoarchitectonic differentiation of these neurons are not modified, it is possible that these alterations result from migration defects and/or from altered synaptic maturation.
authors.affiliation: INSERM U106, IFR des Neurosciences, Bâtiment de Pédiatrie, Hôpital de la Pitié-Salpêtrière, 47 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France.
authors.forename: C
authors.initials: C
authors.lastname: Alvarez
authors.forename: T
authors.initials: T
authors.lastname: Vitalis
authors.forename: E A
authors.initials: EA
authors.lastname: Fon
authors.forename: N
authors.initials: N
authors.lastname: Hanoun
authors.forename: M
authors.initials: M
authors.lastname: Hamon
authors.forename: I
authors.initials: I
authors.lastname: Seif
authors.forename: R
authors.initials: R
authors.lastname: Edwards
authors.forename: P
authors.initials: P
authors.lastname: Gaspar
authors.forename: O
authors.initials: O
authors.lastname: Cases
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D004298:Dopamine / Q000172:deficiency*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D007150:Immunohistochemistry; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D008995:Monoamine Oxidase / Q000172:deficiency / Q000235:genetics; D009434:Neural Pathways / Q000002:abnormalities / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009479:Neuropeptides; D009638:Norepinephrine / Q000172:deficiency*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D012701:Serotonin / Q000172:deficiency*; D013003:Somatosensory Cortex / Q000002:abnormalities* / Q000166:cytology / Q000378:metabolism*; D020651:Ventral Thalamic Nuclei / Q000002:abnormalities / Q000166:cytology / Q000378:metabolism; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
chemical_list: D002135:Calcium-Binding Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009479:Neuropeptides; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C493453:Slc18a2 protein, mouse; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D012701:Serotonin; D008995:Monoamine Oxidase; D004298:Dopamine; D009638:Norepinephrine