Activity-dependent astrocyte swelling is mediated by pH-regulating mechanisms

Abstract

During neuronal activity in the mammalian brain, the K⁺ released into the synaptic space is initially buffered by the astrocytic compartment. In parallel, the extracellular space (ECS) shrinks, presumably due to astrocytic cell swelling. With the Na⁺/K⁺/2Cl⁻ cotransporter and the Kir4.1/AQP4 complex not required for the astrocytic cell swelling in the hippocampus, the molecular mechanisms underlying the activity-dependent ECS shrinkage have remained unresolved. To identify these molecular mechanisms, we employed ion-sensitive microelectrodes to measure changes in ECS, [K⁺]_o and [H⁺]_o/pH_o during electrical stimulation of rat hippocampal slices. Transporters and receptors responding directly to the K⁺ and glutamate released into the extracellular space (the K⁺/Cl⁻ cotransporter, KCC, glutamate transporters and G protein-coupled receptors) did not modulate the extracellular space dynamics. The -transporting mechanism, which in astrocytes mainly constitutes the electrogenic Na⁺/ cotransporter 1 (NBCe1), is activated by the K⁺-mediated depolarization of the astrocytic membrane. Inhibition of this transporter reduced the ECS shrinkage by ∼25% without affecting the K⁺ transients, pointing to NBCe1 as a key contributor to the stimulus-induced astrocytic cell swelling. Inhibition of the monocarboxylate cotransporters (MCT), like-wise, reduced the ECS shrinkage by ∼25% without compromising the K⁺ transients. Isosmotic reduction of extracellular Cl⁻ revealed a requirement for this ion in parts of the ECS shrinkage. Taken together, the stimulus-evoked astrocytic cell swelling does not appear to occur as a direct effect of the K⁺ clearance, as earlier proposed, but partly via the pH-regulating transport mechanisms activated by the K⁺-induced astrocytic depolarization and the activity-dependent metabolism.

Main Points

• Activity-evoked astrocyte cell swelling does not occur as a direct function of the clearance of synaptically released K⁺ or glutamate.
• The astrocytic swelling is, instead, mediated by the pH-regulating cotransporters of and lactate.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2tBCYD6
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