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

Riccardo Bocchi, Kristof Egervari, Laura Carol-Perdiguer, Beatrice Viale, Charles Quairiaux, Mathias Roo, Michael Boitard, Suzanne Oskouie, Patrick Salmon and Jozsef Z. Kiss ()
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Riccardo Bocchi: University of Geneva Medical School
Kristof Egervari: University of Geneva Medical School
Laura Carol-Perdiguer: University of Geneva Medical School
Beatrice Viale: University of Geneva Medical School
Charles Quairiaux: University of Geneva Medical School
Mathias Roo: University of Geneva Medical School
Michael Boitard: University of Geneva Medical School
Suzanne Oskouie: University of Geneva Medical School
Patrick Salmon: University of Geneva Medical School
Jozsef Z. Kiss: University of Geneva Medical School

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01046-w

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