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

It is well known that the electrical signaling in neuronal networks is modulated by chloride (Cl) fluxes via the inhibitory GABA 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] through either (a) VRAC-mediated release of the inhibitory gliotransmitters, GABA and taurine, which open neuronal GABA 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.