PROJECT: JTC2016: ACRoBAT

Altered Chloride homeostasis in Reactive plasticity upOn BrAin Trauma

Abstract

Progressive network reorganization and altered proliferation may stand for traumatic brain injury (TBI)-related complications, such as post-traumatic epilepsy and cognitive impairment. The proposed project aims at defining the contribution of altered chloride homeostasis and GABAergic transmission in TBI-triggered reactive plasticity mechanisms, from cellular to system levels. Our working hypothesis is that TBI induces changes in the chloride regulatory proteins KCC2 and NKCC1 leading to altered intracellular chloride homeostasis and changes in the polarity of GABAA mediated responses. This leads to hyper-excitability as well as requirement by neurons (principal and interneurons) for BDNF trophic support. This is set by GABAA depolarization dependent p75NTR pro-apoptotic signaling. Interneuron apoptosis also result in hyper-excitability and may increase proliferation in the DG. .A major focus of this project is to understand how these processes may contribute to rhythmopathies and epileptogenesis. We address these questions using a combination of state of the art transgenic tools for both temporal and cell specific control and monitoring of intracellular chloride as well as chloride regulatory proteins. This will be combined with advanced in vivo electrophysiological recordings and time-frequency analysis. Ultimately, we will test the therapeutic relevance of novel compounds acting on KCC2 functional expression.

Keywords

Imaging techniques, Gene targeting in the brain, Stem cells and neural differentiation/cell therapy, Pharmacology, Electrophisiological approaches, GABA, Neurotrophins, interneurons, dentate gyrus, rhythmopathies, proliferation, apotosis

Call topic

External Insults

Proposed runtime

2017 - 2021

Project team

Claudio Rivera (Coordinator)
France (ANR)
Jean Christophe Poncer
France (ANR)
Francois Guillemot
United Kingdom (MRC)
Christian A. Hbner
Germany (BMBF)
Liset Mendes de la Prida
Spain (MINECO)