Doctoral thesis

Molecular controls over cortical interneuron subtype migration

Defense date2014-06-16

The migration of GABAergic inhibitory interneurons plays a critical role in the assembly of cortical circuits, and alterations in this process are associated to psychiatric-relevant phenotypes. In mice about 70% of cortical interneurons are generated in the medial ganglionic eminences (MGE) of the subpallium, whereas about 30% originate from the caudal ganglionic eminences (CGE) and to a smaller extent in the preoptic area (PoA). The molecular mechanisms regulating the migration of MGE-derived interneurons have been the focus of many studies in the field, whereas little is know on molecular pathways controlling CGE-derived interneuron migration. In this work, I aimed to investigate the molecular controls over the migration of cortical interneurons (cINs) preferentially derived from the CGE. Using a microarray screen performed on CGE-derived INs, I found that the ionotropic serotonin receptor 3A (5-HT3AR) is transiently up-regulated in cINs from the CGE as they invade the cortical plate. Fate-mapping experiments revealed that the 5-HT3AR is specifically expressed in CGE but not MGE-derived INs. To assess the role of the 5-HT3AR in the migration of CGE INs, we used a combination of methods, including time-lapse imaging, calcium recordings and genetic manipulations. Functional investigations including calcium imaging and migration assays indicated that CGE INs increased their responsiveness to 5-HT3AR activation specifically during CP invasion. Genetic loss-of-function experiments combined to time-lapse imaging and in vivo grafts revealed a cell-autonomous requirement for the 5-HT3AR in regulating the migration of INs into the cortical plate. Altered migration into the CP due to 5-HT3AR deletion led to the persistent laminar mispositioning of a specific subtype of reelin-expressing interneurons. Interestingly this phenotype could be observed in a mouse model of serotonin depletion, the Tph2-KO mice. Finally, to identify 5-HT3AR-dependent down-stream genes regulating migration of cINs, I performed a microarray screen on CGE-derived cINs from Htr3a-KO mice. Using this strategy, I identified the guidance receptor PlexinA4 as a candidate gene that failed to normally up-regulate in Htr3a-KO cINs specifically during the phase of CP invasion. Functional in vivo studies provided evidence that PlexinA4 regulates the positioning of cINs. Taken together, these results reveal a mechanism whereby the time-specific upregulation of the 5-HT3AR is required for the migration and positioning of cINs into the developing cortex, and suggest that PlexinA4 could be a functional downstream target of the 5-HT3AR. Given the implication of interneuron dysfunction and early-life serotonin dysregulation in vulnerability to neuropsychiatric disorders, the 5-HT3AR represents an interesting and novel cell-type specific developmental target of early-life serotonin.

  • Neuroscience
  • Development
  • Cortex
  • Interneurons
  • GABAergic
  • Cortical circuits
NoteDiplôme commun des univ. de Genève et Lausanne. Thèse en Neurosciences des universités de Genève et de Lausanne
Citation (ISO format)
SREEKANTA MURTHY, Sahana. Molecular controls over cortical interneuron subtype migration. 2014. doi: 10.13097/archive-ouverte/unige:41537
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