Smoothened receptor Signaling regulates the developmental shift of GABA polarity in rat somatosensory cortex

Author:

Delmotte Quentin123,Hamze Mira123,Medina Igor123ORCID,Buhler Emmanuelle24,Zhang Jinwei5,Belgacem Yesser H.23,Porcher Christophe123

Affiliation:

1. Aix-Marseille Univ, INSERM, INMED, Parc Scientifique de Luminy 13273, Marseille, France

2. INSERM (Institut National de la Santé et de la Recherche Médicale) Unité 1249, Marseille, Parc Scientifique de Luminy, 13273 Marseille, France

3. INMED (Institut de Neurobiologie de la Méditerranée), Parc Scientifique de Luminy, 13273 Marseille, France

4. Plateforme Post-Génomique, INMED, 13273 Marseille, France

5. Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories, Exeter, EX4 4PS, UK

Abstract

Sonic Hedgehog (Shh) and its patched-smoothened receptor complex control a variety of functions in the developing central nervous system such as neural cell proliferation and differentiation. Recently, Shh signaling components have been found to be expressed at the synaptic level in the postnatal brain, suggesting a potential role in the regulation of synaptic transmission. Using in utero electroporation of constitutively active and negative-phenotype forms of the Shh signal transducer smoothened (Smo), we studied the role of Smo signaling in the development and maturation of GABAergic transmission in the somatosensory cortex. Our results show that enhancing Smo activity during development accelerates the shift from depolarizing to hyperpolarizing GABA in dependence on functional expression of potassium-chloride cotransporter type 2 (KCC2). On the other hand, blocking Smo activity maintains GABA response in a depolarizing state in mature cortical neurons resulting in altered chloride homeostasis and increased seizure susceptibility. This study reveals an unexpected function of Smo signaling on the regulation of chloride homeostasis through the control of KCC2 cell surface stability and on the timing of the GABA inhibitory/excitatory shift in brain maturation.

Funder

Agence Nationale de la Recherche

European Research Council

Brain and Behavior Research Foundation

Publisher

The Company of Biologists

Subject

Cell Biology

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