Astrocytic chloride regulates brain function in health and disease

Chloride ions (Cl^-) play a pivotal role in synaptic inhibition in the central nervous system, primarily mediated through ionotropic mechanisms. A recent breakthrough emphathizes the significant influence of astrocytic intracellular chloride concentration ([Cl^-]_i) regulation, a field still in its early stages of exploration. Typically, the [Cl^-]_i in most animal cells is maintained at lower levels than the extracellular chloride [Cl^-]_o, a critical balance to prevent cell swelling due to osmotic pressure. Various Cl^- transporters are expressed differently across cell types, fine-tuning the [Cl^-]_i, while Cl^- gradients are utilised by several families of Cl^- channels. Although the passive distribution of ions within cells is governed by basic biophysical principles, astrocytes actively expend energy to sustain [Cl^-]_i at much higher levels than those achieved passively, and much higher than neuronal [Cl^-]_i. Beyond the role in volume regulation, astrocytic [Cl^-]_i is dynamically linked to brain states and influences neuronal signalling in actively behaving animals. As a vital component of brain function, astrocytic [Cl^-]_i also plays a role in the development of disorders where inhibitory transmission is disrupted. This review synthesises the latest insights into astrocytic [Cl^-]_i, elucidating its role in modulating brain function and its implications in various pathophysiological conditions.