Displacement of extracellular chloride by sulfated glycosaminoglycans of the brain’s extracellular matrix

GABA is the primary inhibitory neurotransmitter. Membrane currents evoked by GABAA receptor activation have uniquely small driving forces: their reversal potential (EGABA) is very close to the resting membrane potential. As a consequence, GABAA currents can flow in either direction, depending on both the membrane potential and the local intra and extracellular concentrations of the primary permeant ion, chloride (Cl). Cytoplasmic Cl concentrations vary widely due to displacement of mobile Cl ions by relatively immobile anions. Here we describe new reporters of extracellular chloride (Cl-o) and demonstrate that Cl is displaced in the extracellular space by high and spatially heterogenous concentrations of sulfated glycosaminoglycans. The mean Cl-o is only half the canonical concentration, i.e. the Cl concentration in the cerebrospinal fluid. Cl-o microdomains provide a mechanism to link the highly stable distribution of GAGs in the brain’s extracellular space to neuronal signal processing via the effects on the amplitude and direction of GABAA transmembrane Cl currents.