Abstract
Disinhibition caused by Cl(-) dysregulation is implicated in several neurological disorders. This form of disinhibition, which stems primarily from impaired Cl(-) extrusion through the co-transporter KCC2, is typically identified by a depolarizing shift in GABA reversal potential (E GABA). Here we show, using computer simulations, that intracellular [Cl(-)] exhibits exaggerated fluctuations during transient Cl(-) loads and recovers more slowly to baseline when KCC2 level is even modestly reduced. Using information theory and signal detection theory, we show that increased Cl(-) lability and settling time degrade neural coding. Importantly, these deleterious effects manifest after less KCC2 reduction than needed to produce the gross changes in E GABA required for detection by most experiments, which assess KCC2 function under weak Cl(-) load conditions. By demonstrating the existence and functional consequences of "occult" Cl(-) dysregulation, these results suggest that modest KCC2 hypofunction plays a greater role in neurological disorders than previously believed.