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.
Highlights
Vulnerability to psychiatric disorders is likely to be determined by early-life alterations in the formation and plasticity of neural circuits
We investigated the impact of early-life serotonin transporter (SERT) deficiency on the migration and positioning of caudal ganglionic eminence (CGE)-derived cortical INs in SERT-ko mice and in mice exposed to the SERT inhibitor fluoxetine during the late embryonic period
Early-life SERT deficiency increases the migratory speed of CGE-derived INs commonly dysregulated genes were adenomatosis polyposis coli 2 (Apc2),[32,33] slit homolog 2 (Slit2),[34,35,36] spectrin repeat containing nuclear envelope 2 (Syne2)[37] and frizzled homolog 3 (Fzd3),[38,39] which have previously been shown to regulate
Summary
Vulnerability to psychiatric disorders is likely to be determined by early-life alterations in the formation and plasticity of neural circuits. Cortical microcircuits emerge through sequential cellular events involving the coordinated integration of a wide diversity of neurons in a laminated structure.[1] Cortical neuron subtypes have different embryonic origins and reach their final cortical laminar position through the process of neuronal migration.[1,2] Glutamatergic pyramidal neurons are generated in the ventricular zone of the dorsal pallium and migrate radially towards the pial surface, whereas GABAergic cortical interneurons (INs) are born in a variety of subpallial microdomains and reach the developing cortex through tangential migration.[2,3] Alterations in the migration, maturation and function of GABAergic cortical INs have been detected in rodent models of psychiatric disorders and in postmortem brain tissue from patients with schizophrenia and bipolar disorder.[3,4,5,6]. The molecular and cell-type-specific mechanisms that link early-life SERT deficiency to psychiatric-relevant phenotypes remain to be understood
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