Chloride Regulation: A Dynamic Equilibrium Crucial for Synaptic Inhibition

Fast synaptic inhibition relies on tight regulation of intracellular Cl-. Chloride dysregulation is implicated in several neurological and psychiatric disorders. Beyond mere disinhibition, the consequences of Cl- dysregulation are multifaceted and best understood in terms of a dynamical system involving complex interactions between multiple processes operating on many spatiotemporal scales. This dynamical perspective helps explain many unintuitive manifestations of Cl- dysregulation. Here we discuss how taking into account dynamical regulation of intracellular Cl- is important for understanding how synaptic inhibition fails, how to best detect that failure, why Cl- regulation is energetically so expensive, and the overall consequences for therapeutics.