title: Early-life serotonin dysregulation affects the migration and positioning of cortical interneuron subtypes.
abstract: Early-life deficiency of the serotonin transporter (SERT) gives rise to a wide range of psychiatric-relevant phenotypes; however, the molecular and cellular targets of serotonin dyregulation during neural circuit formation remain to be identified. Interestingly, migrating cortical interneurons (INs) derived from the caudal ganglionic eminence (CGE) have been shown to be more responsive to serotonin-mediated signalling compared with INs derived from the medial ganglionic eminence (MGE). Here we investigated the impact of early-life SERT deficiency on the migration and positioning of CGE-derived cortical INs in SERT-ko mice and in mice exposed to the SERT inhibitor fluoxetine during the late embryonic period. Using confocal time-lapse imaging and microarray-based expression analysis we found that genetic and pharmacological SERT deficiency significantly increased the migratory speed of CGE-derived INs and affected transcriptional programmes regulating neuronal migration. Postnatal studies revealed that SERT deficiency altered the cortical laminar distribution of subtypes of CGE-derived INs but not MGE-derived INs. More specifically, we found that the distribution of vasointestinal peptide (VIP)-expressing INs in layer 2/3 was abnormal in both genetic and pharmacological SERT-deficiency models. Collectively, these data indicate that early-life SERT deficiency has an impact on the migration and molecular programmes of CGE-derived INs, thus leading to specific alterations in the positioning of VIP-expressing INs. These data add to the growing evidence that early-life serotonin dysregulation affects cortical microcircuit formation and contributes to the emergence of psychiatric-relevant phenotypes.
authors.affiliation: Department of Mental Health and Psychiatry, University of Geneva Medical School, Geneva, Switzerland.|Department of Psychiatry and Basic Neurosciences, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Frazer
authors.affiliation: Department of Mental Health and Psychiatry, University of Geneva Medical School, Geneva, Switzerland.|Department of Psychiatry and Basic Neurosciences, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Otomo
authors.affiliation: Department of Mental Health and Psychiatry, University of Geneva Medical School, Geneva, Switzerland.|Department of Psychiatry and Basic Neurosciences, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Dayer
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D018507:Gene Expression Regulation, Developmental; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D001523:Mental Disorders / Q000196:embryology / Q000378:metabolism; D051379:Mice; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
chemical_list: D005473:Fluoxetine; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493231:Slc6a4 protein, mouse