KCC2 into the spotlight: from physiology to pathology
Team “Perinatal Imprintings and Neurodevelopmental Disordes”
This thesis explores the role of potassium-chloride cotransporter (KCC2) encoded in mammals by SLC12A5 gene, in GABAergic sequence during development and its relevance to neurodevelopmental disorders (NDD). Two key questions are addressed: (1) How is KCC2 regulated during development, and (2) What changes in KCC2 properties contribute to pathology?
To answer these questions, we used a combination of molecular, cellular biology, electrophysiology and imaging approaches in the primary culture of rat hippocampal neurons and heterologous cell lines and developmental milestones of rat pups. A key signaling pathway involved in control of KCC2 synthesis and its post-translational regulation both in physiology and pathology is the Brain-derived neurotrophic factor (BDNF) produced in 2 forms ProBDNF and mature BDNF (mBDNF). We demonstrated that ProBDNF and mBDNF have opposing effects on neuronal maturation and behavior. We also report the case of two families including children with severe encephalopathy that is associated with heterozygous composite variants in SLC12A5 gene. The in-vitro investigation of the properties of KCC2 variants found in patients let us suggest an ion-transport independent pathway as a major contributor to NDD.
Together, these findings provide novel insights on the regulatory pathways controlling KCC2-dependnt ion homeostasis and its critical role in pathology formation
Laura Cancedda, Rapportrice – Italian Institute of Technology (IIT), Genova
Sabine Lévi, Rapportrice – Institut du Fer à Moulin-Sorbonne, Paris
Amy Mctague, Examinatrice – University College London
Jean Christophe Roux, Président du jury – MMG-UMR1251, Marseille
Christophe Porcher, Directeur de thèse – Inmed, Marseille
Igor Medyna, Co-Directeur de thèse – Inmed, Marseille
Monday 11 December 2023 at 1pm – Inmed conference room