Project R-1131

Title

Inhibitory neurotransmitters as communication signals between the nervous and the immune systems

Abstract

Besides their classical role in mediating fast inhibitory neurotransmission within the central nervous system, increasing evidence suggests that ã aminobutyric acid (GABA) and glycine, the two main amino acid inhibitory neurotransmitters, could also fulfil much broader roles. In that respect, recent works have demonstrated their implication in the development of neuronal cells and their progenitors. GABA and glycine, and their interacting proteins, have also been described on non-neuronal cells of the nervous system, such as astrocytes and oligodendrocytes, and even outside the nervous system, e.g. on immune cells. In these non-neuronal systems, the available information about the potential role of GABA and glycine as signalling molecules remains, however, very incomplete. Therefore, the first aim of this project is to better document the role of the inhibitory neurotransmitters, GABA and glycine, and their interacting proteins on non-neuronal cells of the central nervous system (CNS) and on immune cells. To achieve this aim, we will characterize, at the molecular, morphological and functional levels, GABA and glycine, as well as their synthesizing and degradating enzymes, their ionotropic receptors and their transporters, focussing on oligodendrocytes and their progenitors for the nervous system and on lymphocytes (B and T), macrophages and microglial cells for the immune system. We will also investigate the influence of amino acid inhibitory neurotransmitters and their receptors on specific properties of the target cells, e.g. the membrane organization of oligodendrocytes, immune-mediated oligodendrocyte progenitor injury, cytokine production by immune cells, etc. Experiments will be performed mainly on in vitro, but also on ex vivo models, e.g. brain slices from normal and transgenic mice (eGFP-CNPase or ├Glra2) using an array of techniques available in the BIOMED research centre (molecular biology, biochemistry, immunocyto- and histochemistry, microfluorimetry, patch-clamping and several biological activity assays). In the field of neuroimmunology, emphasis has been put forward during the last years on immune-related signals, such as cytokines for example. With the exception of glutamate, the main amino acid excitatory neurotransmitter, much less is known of what type of influence could have nervous system-related signals. Therefore, a second aim of this project will be to examine if inhibitory neurotransmitters could serve as signalling molecules between the nervous and the immune systems. To answer that question, we intend to evaluate the influence of GABA and glycine signalling, as evidenced in the first part of our project, in conditions where (dys)function of immune-nervous system communication is known to play a key role, i.e. multiple sclerosis (MS). For this purpose, we will use an animal model of this disease, i.e. Experimental Allergic Encephalomyelitis (EAE), and human material obtained from MS patients.

Period of project

16 September 2006 - 15 September 2009