Serotonin receptor 3A controls interneuron migration into the neocortex.

Sahana Murthy,Alexandre Dayer,Sarah Frazer,Greta Limoni,Pascal Chameau,Mathieu Niquille,Tania Vitalis,Johannes A Van Hooft,Nicolas Hurni

doi:10.1038/ncomms6524

Abstract

Neuronal excitability has been shown to control the migration and cortical integration of reelin-expressing cortical interneurons (INs) arising from the caudal ganglionic eminence (CGE), supporting the possibility that neurotransmitters could regulate this process. Here we show that the ionotropic serotonin receptor 3A (5-HT3AR) is specifically expressed in CGE-derived migrating interneurons and upregulated while they invade the developing cortex. Functional investigations using calcium imaging, electrophysiological recordings and migration assays indicate that CGE-derived INs increase their response to 5-HT3AR activation during the late phase of cortical plate invasion. Using genetic loss-of-function approaches and in vivo grafts, we further demonstrate that the 5-HT3AR is cell autonomously required for the migration and proper positioning of reelin-expressing CGE-derived INs in the neocortex. Our findings reveal a requirement for a serotonin receptor in controlling the migration and laminar positioning of a specific subtype of cortical IN.

Highlights

Neuronal excitability has been shown to control the migration and cortical integration of reelin-expressing cortical interneurons (INs) arising from the caudal ganglionic eminence (CGE), supporting the possibility that neurotransmitters could regulate this process
Calcium imaging and electrophysiological recordings indicate that the 5-HT3AR is functional in CGEderived interneurons (cINs) during cortical plate (CP) invasion and that 5-HT3AR activation increases their migratory speed during this late phase of migration
Htr3a-GFP þ INs were observed at E14.5 exiting the subpallium by forming a tangential stream of migratory INs located in the pallial subventricular zone (SVZ) and invading the CP by E17.5 (Fig. 1e)

Summary

Introduction

Neuronal excitability has been shown to control the migration and cortical integration of reelin-expressing cortical interneurons (INs) arising from the caudal ganglionic eminence (CGE), supporting the possibility that neurotransmitters could regulate this process. Using genetic loss-of-function approaches and in vivo grafts, we further demonstrate that the 5-HT3AR is cell autonomously required for the migration and proper positioning of reelin-expressing CGE-derived INs in the neocortex. Recent in vivo data have demonstrated that neuronal excitability controls the laminar positioning of reelin-expressing CGE-derived INs18 These data support the possibility that cellextrinsic factors such as neurotransmitters could regulate early activity of migrating cINs and control their final laminar positioning. To investigate the molecular mechanisms regulating different steps in the migration of cINs, we performed a microarray gene expression analysis on INs preferentially derived from the CGE at three distinct developmental stages of the migratory process. We find that genetic deletion of the 5-HT3AR led to the persistent laminar mispositioning of reelin-expressing CGE-derived INs

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