Perturbed Wnt signaling leads to neuronal migration delay, altered interhemispheric connections and impaired social behavior

Riccardo Bocchi,Beatrice Viale,Patrick Salmon,Michael Boitard,Suzanne Oskouie,Mathias De Roo,Jozsef Z Kiss,Laura Carol-Perdiguer,Kristof Egervari,Charles Quairiaux

doi:10.1038/s41467-017-01046-w

Riccardo Bocchi, Beatrice Viale + Show 8 more

Open Access

https://doi.org/10.1038/s41467-017-01046-w

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Journal: Nature Communications	Publication Date: Oct 27, 2017
Citations: 64	License type: open-access

Affiliation: University of Geneva

Abstract

Perturbed neuronal migration and circuit development have been implicated in the pathogenesis of neurodevelopmental diseases; however, the direct steps linking these developmental errors to behavior alterations remain unknown. Here we demonstrate that Wnt/C-Kit signaling is a key regulator of glia-guided radial migration in rat somatosensory cortex. Transient downregulation of Wnt signaling in migrating, callosal projection neurons results in delayed positioning in layer 2/3. Delayed neurons display reduced neuronal activity with impaired afferent connectivity causing permanent deficit in callosal projections. Animals with these defects exhibit altered somatosensory function with reduced social interactions and repetitive movements. Restoring normal migration by overexpressing the Wnt-downstream effector C-Kit or selective chemogenetic activation of callosal projection neurons during a critical postnatal period prevents abnormal interhemispheric connections as well as behavioral alterations. Our findings identify a link between defective canonical Wnt signaling, delayed neuronal migration, deficient interhemispheric connectivity and abnormal social behavior analogous to autistic characteristics in humans.

Highlights

Perturbed neuronal migration and circuit development have been implicated in the pathogenesis of neurodevelopmental diseases; the direct steps linking these developmental errors to behavior alterations remain unknown
We showed that dynamically regulated activity levels of Wnt/βcatenin as well as non-canonical Wnt signaling are essential in the control of multipolar-to-bipolar transition of layer 2/3 pyramidal neurons during the initial phase of radial migration[18]
We introduced this reporter into precursors of layer 2/3 pyramidal neurons of the somatosensory cortex using intrauterine electroporation at embryonic day (E) 18

Summary

Introduction

Perturbed neuronal migration and circuit development have been implicated in the pathogenesis of neurodevelopmental diseases; the direct steps linking these developmental errors to behavior alterations remain unknown. Delayed neurons display reduced neuronal activity with impaired afferent connectivity causing permanent deficit in callosal projections Animals with these defects exhibit altered somatosensory function with reduced social interactions and repetitive movements. While the structural and functional consequences of a permanent disruption of neuronal migration are well documented[7], little is known about how transient migration delays without apparent structural defects may impact on the subsequent development of cortical circuits. This is an important issue since it has been suggested that neuronal migration disorders may play a role in the pathogenesis of perturbed neuronal connectivity underlying neuropsychiatric diseases, including autism spectrum disorders (ASD) and schizophrenia[8,9,10,11,12]. Postnatal chemogenetic induction of neuronal activity was able to rescue interhemispheric projections and social behavior, raising the possibility of correcting circuit alterations during the postnatal period

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