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This Week in The Journal

GABAergic receptors form the cornerstone of inhibitory synaptic signaling in the brain. Classically, ionotropic GABAA receptors pass inward chloride-dominated currents, effectively dampening neural activity by stabilizing or hyperpolarizing the cell’s membrane potential. A more positive reversal potential could lead to loss of inhibition or, in some circumstances, even tip GABA’s effect toward neural excitation. The direction of current—and its effect on the cell— depends on the balance of chloride ions on either side of the membrane, which is generally thought to be consistent throughout a given cell. But for years, researchers have reported a range of reversal potentials through GABAA channels. Now Rahmati, Normoyle, et al. definitively show that the variation depends on stable intracellular chloride microdomains that arise from variations in structural anionic biopolymers such as the cytoplasmic protein actin. The authors used an array of techniques to measure chloride concentration in hippocampal pyramidal neurons, including two-photon microscopy of ratiometric, transgenic chloride-sensitive fluorophores, and fluorescence lifetime imaging of chloride-sensitive dyes. Fluorophore imaging indicated that subcellular concentration of chloride varied significantly across a single neuron, and that these microdomains remained stable over time, even following a large transient chloride flux. In addition, the authors made electrophysiological recordings from an individual pyramidal cell while stimulating presynaptic interneurons, each of which made a synapse on the same pyramidal neuron. Remarkably, each interneuron evoked GABAergic currents with unique chloride reversal potentials over a 23 mV range. Although chloride microdomains have been investigated for decades, inquiry has often centered around the impact of ion transporters on chloride equilibrium. But here, the authors follow up on their 2014 finding that impermeant ions, such as those locked up in polymers, contribute to chloride homeostasis. In the current study, the researchers imaged single hippocampal neurons while blocking the cation–chloride cotransporters (CCCs) NKCC1 and KCC2 and saw no effect on the chloride microdomain distribution, suggesting they were not determined by local variations in cation–chloride transport rates. When they manipulated actin dynamics to favor depolymerization, however, microdomains were disrupted, presumably due to reorganization of the large, negatively charged macromolecules. The microdomains allow a single neuron to respond differently to multiple GABAergic interneurons and perhaps to each individual synaptic input. The consequence could be a functional expansion of GABA signaling to include not only hyperpolarization but potentially amplification of excitatory signals.