– Role of Sonic Hedgehog pathway in postnatal hippocampal transmission and

GABAergic developmental shift –

Abstract

During this thesis, we studied what links may exist between Sonic Hedgehog (Shh) pathway, a morphogenic molecule which also seems to participate in many neurotrophic functions after birth, and GABAergic transmission.

First, by acute activation of Shh pathway with an agonist, we were able to show it can modulate primitive network activities in the immature hippocampus, Giant Depolarizing Potentials (GDP). These activities are made up with GABAergic and glutamatergic components. We demonstrate that Shh pathway only acts on GABAergic transmission and involves release of the main neurotrophic factor in the brain, Brain-Derived-Neurotrophic-Factor (BDNF).
Then, we have studied long-term impact of Shh pathway modulation by electroporation, in the somatosensory cortex of rats, of constitutively active or dominant negative receptor. We observed that Shh pathway inhibition delays GABAergic maturation by destabilizing endocytosis of membranous KCC2, thus resulting in a higher chloride concentration even three weeks after birth. Conversely, activation of Smo receptor accelerates maturation sequence, causing hyperpolarized GABA in young animals, with a low intracellular chloride concentration.

These results reveal new perspectives for Shh pathway on chloride homeostasis through KCC2 membrane trafficking, and consequently on GABA polarity regulation during postnatal development.

Jury
Martial RUAT (DR) – Rapporteur – Institut NeuroPSI, Gif sur Yvette
Pascal Branchereau (PU) – Rapporteur – Incia, Bordeaux
Heather McLean (MCU) – Examinatrice – Insitut de Neurosciences Paris Saclay, Orsay
Pascale Chavis (DR) – Présidente – Inmed, Marseille
Christophe Porcher (PR) – Directeur de thèse – Inmed, Marseille

Inmed meeting room, Monday October 12th, 2 pm