The signaling role for chloride in the bidirectional communication between neurons and astrocytes

Abstract

It is well known that the electrical signaling in neuronal networks is modulated by chloride (Cl^-) fluxes via the inhibitory GABA_A and glycine receptors. Here, we discuss the putative contribution of Cl^- fluxes and intracellular Cl^- to other forms of information transfer in the CNS, namely the bidirectional communication between neurons and astrocytes. The manuscript (i) summarizes the generic functions of Cl^- in cellular physiology, (ii) recaps molecular identities and properties of Cl^- transporters and channels in neurons and astrocytes, and (iii) analyzes emerging studies implicating Cl^- in the modulation of neuroglial communication. The existing literature suggests that neurons can alter astrocytic Cl^- levels in a number of ways; via (a) the release of neurotransmitters and activation of glial transporters that have intrinsic Cl^- conductance, (b) the metabotropic receptor-driven changes in activity of the electroneutral cation-Cl^- cotransporter NKCC1, and (c) the transient, activity-dependent changes in glial cell volume which open the volume-regulated Cl^-/anion channel VRAC. Reciprocally, astrocytes are thought to alter neuronal [Cl^-]_i through either (a) VRAC-mediated release of the inhibitory gliotransmitters, GABA and taurine, which open neuronal GABA_A and glycine receptor/Cl^- channels, or (b) the gliotransmitter-driven stimulation of NKCC1. The most important recent developments in this area are the identification of the molecular composition and functional heterogeneity of brain VRAC channels, and the discovery of a new cytosolic [Cl^-] sensor - the Wnk family protein kinases. With new work in the field, our understanding of the role of Cl^- in information processing within the CNS is expected to be significantly updated.

Keywords: Chloride channels; Chloride homeostasis; KCC; NKCC; Neuron-astrocyte communication; VRAC; WNK.